Spirocyclic compounds as tryptophan hydroxylase inhibitors

ABSTRACT

The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.

FIELD OF THE INVENTION

The present invention is directed to spirocyclic compounds which areinhibitors of tryptophan hydroxylase (TPH), particularly isoform 1(TPH1), that are useful in the treatment of diseases or disordersassociated with peripheral serotonin including, for example,gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic,and low bone mass diseases, as well as serotonin syndrome, and cancer.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter thatmodulates central and peripheral functions by acting on neurons, smoothmuscle, and other cell types. 5-HT is involved in the control andmodulation of multiple physiological and psychological processes. In thecentral nervous system (CNS), 5-HT regulates mood, appetite, and otherbehavioral functions. In the GI system, 5-HT plays a general prokineticrole and is an important mediator of sensation (e.g., nausea andsatiety) between the GI tract and the brain. Dysregulation of theperipheral 5-HT signaling system has been reported to be involved in theetiology of several conditions (see for example: Mawe, G. M. & Hoffman,J. M. Serotonin Signalling In The Gut-functions, Dysfunctions AndTherapeutic Targets. Nature Reviews. Gastroenterology & Hepatology 10,473-486 (2013); Gershon, M. D. 5-hydroxytryptamine (serotonin) In TheGastrointestinal Tract. Current Opinion in Endocrinology, Diabetes, andObesity 20, 14-21 (2013); Lesurtel, M., Soll, C., Graf, R. & Clavien,P.-A. Role of Serotonin In The Hepato-gastrointestinal Tract: An OldMolecule For New Perspectives. Cellular And Molecular Life Sciences:CMLS 65, 940-52 (2008)). These include osteoporosis (e.g. Kode, A. etal. FOXO1 Orchestrates The Bone-suppressing Function Of Gut-derivedSerotonin. The Journal of Clinical Investigation 122, 3490-503 (2012);Yadav, V. K. et al. Pharmacological Inhibition Of Gut-derived SerotoninSynthesis Is A Potential Bone Anabolic Treatment For Osteoporosis.Nature Medicine 16, 308-12 (2010); Yadav, V. K. et al. Lrp5 ControlsBone Formation By Inhibiting Serotonin Synthesis In The Duodenum. Cell135, 825-37 (2008)), cancer (e.g. Liang, C. et al. Serotonin PromotesThe Proliferation Of Serum-deprived Hepatocellular Carcinoma Cells ViaUpregulation Of FOXO3a. Molecular Cancer 12, 14 (2013); Soil, C. et al.Serotonin Promotes Tumor Growth In Human Hepatocellular Cancer.Hepatology 51, 1244-1254 (2010); Pai, V. P et al. Altered SerotoninPhysiology In Human Breast Cancers Favors Paradoxical Growth And CellSurvival. Breast Cancer Research: BCR 11, R81 (2009); Engelman, K.,Lovenberg, W. & Sjoerdsma, A. Inhibition Of Serotonin Synthesis ByPara-chlorophenylalanine In Patients With The Carcinoid Syndrome. TheNew England Journal of Medicine 277, 1103-8 (1967)), cardiovascular(e.g. Robiolio, P. A. et al. Carcinoid Heart Disease: Correlation ofHigh Serotonin Levels With Valvular Abnormalities Detected by CardiacCatheterization and Echocardiography. Circulation 92, 790-795 (1995).),diabetes (e.g. Sumara, G., Sumara, O., Kim, J. K. & Karsenty, G.Gut-derived Serotonin Is A Multifunctional Determinant To FastingAdaptation. Cell Metabolism 16, 588-600 (2012)), atherosclerosis (e.g.Ban, Y. et al. Impact Of Increased Plasma Serotonin Levels And CarotidAtherosclerosis On Vascular Dementia. Atherosclerosis 195, 153-9(2007)), as well as gastrointestinal (e.g. Manocha, M. & Khan, W. I.Serotonin and GI Disorders: An Update on Clinical and ExperimentalStudies. Clinical and Translational Gastroenterology 3, e13 (2012);Ghia, J.-E. et al. Serotonin Has A Key Role In Pathogenesis OfExperimental Colitis. Gastroenterology 137, 1649-60 (2009); Sikander,A., Rana, S. V. & Prasad, K. K. Role Of Serotonin In GastrointestinalMotility And Irritable Bowel Syndrome. Clinica Chimica Acta;International Journal of Clinical Chemistry 403, 47-55 (2009); Spiller,R. Recent Advances In Understanding The Role Of Serotonin InGastrointestinal Motility In Functional Bowel Disorders: Alterations In5-HT Signalling And Metabolism In Human Disease. Neurogastroenterologyand Motility: The Official Journal of The European GastrointestinalMotility Society 19 Suppl 2, 25-31 (2007); Costedio, M. M., Hyman, N. &Mawe, G. M. Serotonin And Its Role In Colonic Function And InGastrointestinal Disorders. Diseases of the Colon and Rectum 50, 376-88(2007); Gershon, M. D. & Tack, J. The Serotonin Signaling System: FromBasic Understanding To Drug Development For Functional GI Disorders.Gastroenterology 132, 397-414 (2007); Mawe, G. M., Coates, M. D. &Moses, P. L. Review Article: Intestinal Serotonin Signalling InIrritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics 23,1067-76 (2006); Crowell, M. D. Role Of Serotonin In The PathophysiologyOf The Irritable Bowel Syndrome. British Journal of Pharmacology 141,1285-93 (2004)), pulmonary (e.g. Lau, W. K. W. et al. The Role OfCirculating Serotonin In The Development Of Chronic ObstructivePulmonary Disease. PloS One 7, e31617 (2012); Egermayer, P., Town, G. I.& Peacock, A. J. Role Of Serotonin In The Pathogenesis Of Acute AndChronic Pulmonary Hypertension. Thorax 54, 161-168 (1999)), inflammatory(e.g. Margolis, K. G. et al. Pharmacological Reduction of Mucosal butNot Neuronal Serotonin Opposes Inflammation In Mouse Intestine. Gutdoi:10.1136/gutjnl-2013-304901 (2013); Duerschmied, D. et al. PlateletSerotonin Promotes The Recruitment Of Neutrophils To Sites Of AcuteInflammation In Mice. Blood 121, 1008-15 (2013); Li, N. et al. SerotoninActivates Dendritic Cell Function In The Context Of Gut Inflammation.The American Journal of Pathology 178, 662-71 (2011)), or liver diseasesor disorders (e.g. Ebrahimkhani, M. R. et al. Stimulating Healthy TissueRegeneration By Targeting The 5-HT2B Receptor In Chronic Liver Disease.Nature Medicine 17, 1668-73 (2011)). The large number of pharmaceuticalagents that block or stimulate the various 5-HT receptors is alsoindicative of the wide range of medical disorders that have beenassociated with 5-HT dysregulation (see for example: Wacker, D. et al.Structural Features For Functional Selectivity At Serotonin Receptors.Science (New York N.Y.) 340, 615-9 (2013)).

The rate-limiting step in 5-HT biosynthesis is the hydroxylation oftryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase(TPH; EC 1.14.16.4) in the presence of the cofactor(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). The resulting oxidizedproduct, 5-hydroxytryptophan (5-HTT) is subsequently decarboxylated byan aromatic amino acid decarboxylase (AAAD; EC 4.1.1.28) to produce5-HT. Together with phenylalanine hydroxylase (PheOH) and tyrosinehydroxylase (TH), TPH belongs to the pterin-dependent aromatic aminoacid hydroxylase family.

Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have beenidentified. TPH1 is primarily expressed in the pineal gland andnon-neuronal tissues, such as enterochromaffin (EC) cells located in thegastrointestinal (GI) tract. TPH2 (the dominant form in the brain) isexpressed exclusively in neuronal cells, such as dorsal raphe ormyenteric plexus cells. The peripheral and central systems involved in5-HT biosynthesis are isolated, with 5-HT being unable to cross theblood-brain barrier. Therefore, the pharmacological effects of 5-HT canbe modulated by agents affecting TPH in the periphery, mainly TPH1 inthe gut.

A small number of phenylalanine-derived TPH1 inhibitors are known. Oneexample, p-chlorophenylalanine (pCPA), a very weak and unselectiveirreversible inhibitor of TPH, has proven effective in treatingchemotherapy-induced emesis, as well as diarrhea, in carcinoid tumorpatients. However, pCPA is distributed centrally and, as a result, itsadministration has been linked to the onset of depression and otheralterations of CNS functions in patients and animals. p-Ethynylphenylalanine is a more selective and more potent TPH inhibitor thanpCPA (Stokes, A. H. et al. p-Ethynylphenylalanine: A Potent Inhibitor OfTryptophan Hydroxylase. Journal of Neurochemistry 74, 2067-73 (2000),but also affects central 5-HT production and, like pCPA, is believed toirreversibly interfere with the synthesis of TPH (and possibly otherproteins).

More recently, bulkier phenylalanine-derived TPH inhibitors have beenreported to reduce intestinal 5-HT concentration without affecting brain5-HT levels (Zhong, H. et al. Molecular dynamics simulation oftryptophan hydroxylase-1: binding modes and free energy analysis tophenylalanine derivative inhibitors. International Journal of MolecularSciences 14, 9947-62 (2013); Ouyang, L. et al. Combined Structure-BasedPharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds asTPH1 Inhibitors. International Journal of Molecular Sciences 13, 5348-63(2012); Camilleri, M. LX-1031, A Tryptophan 5-hydroxylase Inhibitor, AndIts Potential In Chronic Diarrhea Associated With Increased Serotonin.Neurogastroenterology and Motility: The Official Journal of The EuropeanGastrointestinal Motility Society 23, 193-200 (2011); Cianchetta, G. etal. Mechanism of Inhibition of Novel Tryptophan Hydroxylase InhibitorsRevealed by Co-crystal Structures and Kinetic Analysis. Current chemicalgenomics 4, 19-26 (2010); Jin, H. et al. Substituted3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic Acids As NovelTryptophan Hydroxylase Inhibitors. Bioorganic & Medicinal ChemistryLetters 19, 5229-32 (2009); Shi, Z.-C. et al. Modulation Of PeripheralSerotonin Levels By Novel Tryptophan Hydroxylase Inhibitors For ThePotential Treatment Of Functional Gastrointestinal Disorders. Journal ofmedicinal chemistry 51, 3684-7 (2008); Liu, Q. et al. Discovery AndCharacterization of Novel Tryptophan Hydroxylase Inhibitors ThatSelectively Inhibit Serotonin Synthesis In The Gastrointestinal Tract.The Journal of Pharmacology and Experimental Therapeutics 325, 47-55(2008)).

There is a current need to selectively reduce intestinal 5-HT levels asa means for treating and preventing 5-HT-associated diseases. The TPH1inhibitors described herein are intended to address this need.

SUMMARY OF THE INVENTION

The present invention relates to a TPH-inhibiting compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present invention further relates to a pharmaceutical compositioncomprising a TPH-inhibiting compound of the invention, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.

The present invention further relates to a method of inhibiting TPH,such as TPH1, by contacting the TPH enzyme with a compound of Formula I,or a pharmaceutically acceptable salt thereof.

The present invention further relates to a method of lowering peripheralserotonin in a patient comprising administering to the patient aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

The present invention further relates to a method of treating orpreventing a disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

The present invention further relates to a compound of Formula I, or apharmaceutically acceptable salt thereof, for use in the treatment orprevention of disease in a patient.

The present invention further relates to use of a compound of Formula Ior a pharmaceutically acceptable salt thereof, for the preparation of amedicament for the treatment or prevention of disease in a patient.

DETAILED DESCRIPTION

Compounds

The present invention relates to a TPH-inhibiting compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4 to 10-memberedheterocycloalkyl, or 5 to 10-membered heteroaryl;

L is O or NR⁴;

W is N or CR⁵;

X is N or CR⁶;

Y is N or CR⁷;

wherein only one of X and Y is N;

R¹ is H, C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, phenyl, —(CR⁸R⁹)_(p)OC(O)R¹⁰,—(CR⁸R⁹)_(p)NR¹¹R¹², or —(CR⁸R⁹)_(p)C(O)NR¹¹R¹², wherein said C₁₋₁₀alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, and phenyl are each optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from F, Cl, Br, CN, C₁₋₄ alkyl,and C₁₋₄haloalkyl;

R² and R³ are each independently selected from H, C₁₋₄ alkyl, and C₁₋₄haloalkyl;

R⁴ is H or C₁₋₄ alkyl;

R⁵ and R⁶ are each independently selected from H, halo, and C₁₋₄ alkyl;

R⁷ is H, C₁₋₄ alkyl, C₂₋₆ alkenyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10membered heteroaryl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, NR¹³R¹⁴,OR¹⁵, C(O)R¹⁶, S(O)_(q)R¹⁷, wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and (5-10membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 substituents selected from halo, C₁₋₄ alkyl, C₂₋₆ alkenyl, amino,C₁₋₄ alkylamino, C₂₋₈ dialkylamino, hydroxy, and C₁₋₄ alkoxy;

R⁸ and R⁹ are each independently selected from H and C₁₋₄ alkyl;

R¹⁰ is C₁₋₆ alkyl optionally substituted by 1, 2 or 3 substituentsindependently selected from C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, OR^(a),and NR^(c)R^(d);

R¹¹ and R¹² are each independently selected from H and C₁₋₆ alkyl;

R¹³ is H or C₁₋₄ alkyl;

R¹⁴ is H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, or(5-10 membered heteroaryl)-C₁₋₄ alkyl, C(O)R^(b1), C(O)OR^(a1),C(O)NR^(c1)R^(d1), S(O)R^(b1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1),wherein said C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and(5-10 membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

or R¹³ and R¹⁴ together with the N atom to which they are attached forma 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected fromC₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are each optionally substitutedby 1, 2, or 3 substituents independently selected from halo, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R¹⁵ is H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, or(5-10 membered heteroaryl)-C₁₋₄ alkyl, wherein said C₁₋₄ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and (5-10membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 substituents independently selected from halo, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R¹⁶ is C₁₋₄ alkyl or NR^(18a)R^(18b) wherein said C₁₋₄ alkyl isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR¹, S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R¹⁷ is C₁₋₄ alkyl, NR^(18a)R^(18b), or OR^(18c), wherein said C₁₋₄ alkylis optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-6 membered heteroaryl, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R^(18a) and R^(18b) are each independently selected from H and C₁₋₄alkyl wherein said C₁₋₄ alkyl is optionally substituted by 1, 2, or 3substituents independently selected from halo, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c4)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

or R^(18a) and R^(18b) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R^(18c) is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, or(5-10 membered heteroaryl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and (5-10membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(A) is H, Cy¹, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆alkyl and C₂₋₆ alkenyl are each optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from Cy¹, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2);

R^(B) is H, Cy², halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), or S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆alkyl and C₂₋₆ alkenyl are each optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from Cy², halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c1)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

R^(C) and R^(D) are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl and C₂₋₆ alkenyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

Cy¹ and Cy² are each independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4,or 5 substituents independently selected from R^(Cy);

each R^(Cy) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, C₁₋₆ alkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a), R^(a1), R^(a2), R^(a3), R^(a4), and R^(a5) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, halo,CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

each R^(b1), R^(b2), R^(b3), R^(b4), and R^(b5) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, halo,CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)₂R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

each R^(c), R^(d), R^(c1), R^(d1), R^(c2), R^(d2), R^(c3), R^(d3),R^(c4), R^(d4), R^(c5), and R^(d5) is independently selected from H,C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from C₁₋₄ alkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, CN,OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, CN,OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl,C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)C(O)OR^(a6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are each optionally substitutedby 1, 2, or 3 substituents independently selected from halo, CN,OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₃₋₇ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein said C₁₋₄ alkyl,C₂₋₄ alkenyl, C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl are each optionally substituted by 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, and di(C₁₋₄alkyl)amino;

n is 1 or 2;

p is 1, 2, or 3; and

q is 1 or 2;

wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl groupoptionally comprises 1, 2, or 3 oxo substituents, wherein each oxosubstituent that is present is substituted on a ring-forming carbon,nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkylgroup.

In some embodiments, the present invention relates to a TPH-inhibitingcompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4 to 10-memberedheterocycloalkyl, or 5 to 10-membered heteroaryl;

L is O or NR⁴;

W is N or CR⁵;

X is N or CR⁶;

Y is N or CR⁷;

wherein only one of X and Y is N;

R¹ is H, C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, phenyl, —(CR⁸R⁹)_(p)OC(O)R¹⁰,—(CR⁸R⁹)^(p)NR¹¹R¹², or —(CR⁸R⁹)_(p)C(O)NR¹¹R¹², wherein said C₁₋₁₀alkyl, C₃₋₁₀ cycloalkyl, and phenyl are each optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, CN,C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

R² and R³ are each independently selected from H, C₁₋₄ alkyl, and C₁₋₄haloalkyl;

R⁴ is H or C₁₋₄ alkyl;

R⁵ and R⁶ are each independently selected from H, halo, and C₁₋₄ alkyl;

R⁷ is H, C₁₋₄ alkyl, C₂₋₆ alkenyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10membered heteroaryl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, NR¹³R¹⁴,OR¹⁵, C(O)R¹⁶, S(O)_(q)R¹⁷, wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and (5-10membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 substituents selected from halo, C₁₋₄ alkyl, C₂₋₆ alkenyl, amino,C₁₋₄ alkylamino, C₂₋₈ dialkylamino, hydroxy, and C₁₋₄ alkoxy;

R⁸ and R⁹ are each independently selected from H and C₁₋₄ alkyl;

R¹⁶ is C₁₋₆ alkyl optionally substituted by 1, 2 or 3 substituentsindependently selected from C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, OR^(a),and NR^(c)R^(d);

R¹¹ and R¹² are each independently selected from H and C₁₋₆ alkyl;

R¹³ is H or C₁₋₄ alkyl;

R¹⁴ is H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, or(5-10 membered heteroaryl)-C₁₋₄ alkyl, C(O)R^(b1), C(O)OR^(a1),C(O)NR^(c1)R^(d1), S(O)R^(b1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1),wherein said C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and(5-10 membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

or R¹³ and R¹⁴ together with the N atom to which they are attached forma 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected fromC₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1) and S(O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are each optionally substitutedby 1, 2, or 3 substituents independently selected from halo, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R¹⁵ is H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, or(5-10 membered heteroaryl)-C₁₋₄ alkyl, wherein said C₁₋₄ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and (5-10membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 substituents independently selected from halo, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R¹⁶ is C₁₋₄ alkyl or NR^(18a)R^(18b) wherein said C₁₋₄ alkyl isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R¹⁷ is C₁₋₄ alkyl, NR^(18a)R^(18b), or OR^(18c), wherein said C₁₋₄ alkylis optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ acyl, 5-6 membered heteroaryl, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R^(18a) and R^(18b) are each independently selected from H and C₁₋₄alkyl wherein said C₁₋₄ alkyl is optionally substituted by 1, 2, or 3substituents independently selected from halo, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c4)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

or R^(18a) and R^(18b) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1) S(O)₂R^(b1), NR^(c1) S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), and S(O)₂NR^(c1)R^(d1);

R^(18c) is H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, or(5-10 membered heteroaryl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, 5-10 membered heteroaryl, and (5-10membered heteroaryl)-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(A) is H, Cy¹, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆alkyl and C₂₋₆ alkenyl are each optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from Cy¹, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2);

R^(B) is H, Cy², halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), or S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆alkyl and C₂₋₆ alkenyl are each optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from Cy², halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c1)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

R^(C) and R^(D) are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl and C₂₋₆ alkenyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

Cy¹ and Cy2 are each independently selected from C6-10 aryl, C3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4,or 5 substituents independently selected from RCy;

each R^(Cy) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, C₁₋₆ alkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a), R^(a1), R^(a2), R^(a3), R^(a4), and R^(a5) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, halo,CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

each R^(b1), R^(b2), R^(b3), R^(b4), and R^(b5) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,(5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, halo,CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

each R^(c), R^(d), R^(c1), R^(d1), R^(c2), R^(d2), R^(c3), R^(d3),R^(c4), R^(d4), R^(c5), and R^(d5) is independently selected from H,C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkylare each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from C₁₋₄ alkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, CN,OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, halo, CN,OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₃₋₇ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl, wherein said C₁₋₄ alkyl,C₂₋₄ alkenyl, C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl are each optionally substituted by 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, and di(C₁₋₄ alkyl)amino;

n is 1 or 2;

p is 1, 2, or 3; and

q is 1 or 2;

wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl groupoptionally comprises 1, 2, or 3 oxo substituents, wherein each oxosubstituent that is present is substituted on a ring-forming carbon,nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkylgroup.

In some embodiments, L is O.

In some embodiments, L is NR⁴.

In some embodiments, W is CR⁵; X is N; and Y is CR⁷.

In some embodiments, W is N; X is N; and Y is CR⁷.

In some embodiments, W is CR⁵; X is CR⁶; and Y is N.

In some embodiments, W is CR⁵; X is CR⁶; and Y is CR⁷.

In some embodiments, W is N; X is CR⁶; and Y is CR⁷.

In some embodiments, R² is H and R³ is H.

In some embodiments, R² is H and R³ is C₁₋₄ alkyl.

In some embodiments, R² is H and R³ is methyl.

In some embodiments, R² is H and R³ is C₁₋₄ haloalkyl.

In some embodiments, R² is H and R³ is trifluoromethyl.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, R¹ is H.

In some embodiments, R¹ is C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, phenyl,—(CR⁸R⁹)_(p)OC(O)R¹⁰, —(CR⁸R⁹)_(p)NR¹¹R¹², or —(CR⁸R⁹)_(p)C(O)NR¹¹R¹²,wherein said C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, and phenyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from F, Cl, Br, CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

In some embodiments, R¹ is C₁₋₁₀ alkyl.

In some embodiments, R¹ is ethyl.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is other than H.

In some embodiments, R⁷ is C₁₋₄ alkyl, NR¹³R¹⁴, or OR¹⁵.

In some embodiments, R⁷ is NR¹³R¹⁴.

In some embodiments, R⁷ is NH₂.

In some embodiments, R⁷ is C₁₋₄ alkyl.

In some embodiments, R⁷ is OR¹⁵.

In some embodiments, Ring A is C₃₋₁₀cycloalkyl.

In some embodiments, Ring A is C₆₋₁₀ aryl.

In some embodiments, Ring A is phenyl.

In some embodiments, Ring A is 4 to 10-membered heterocycloalkyl.

In some embodiments, Ring A is phenyl, adamantanyl, naphthyl,1,2,3,4-tetrahydroquinoxalinyl, 3,4-dihydroquinazolinyl,1,2,3,4-tetrahydroquinazolinyl, or pyridyl.

In some embodiments, Ring A is 5 to 10-membered heteroaryl.

In some embodiments, at least one of R^(A), R^(B), R^(C), and R^(D) isother than hydrogen.

In some embodiments, at least two of R^(A), R^(B), R^(C), and R^(D) areother than hydrogen.

In some embodiments, R^(A) is Cy¹.

In some embodiments, R^(A) is C₆₋₁₀ aryl or 5-10 membered heteroaryl,each of which is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from R^(Cy).

In some embodiments, R^(A) is 5-10 membered heteroaryl optionallysubstituted by 1, 2, 3, 4, or 5 substituents independently selected fromR^(Cy).

In some embodiments, R^(A) is 5 to 6-membered heteroaryl optionallysubstituted by 1, 2, or 3 substituents independently selected fromR^(Cy).

In some embodiments, R^(A) is pyrazolyl which is optionally substitutedby 1, 2, 3, 4, or 5 substituents independently selected from R^(Cy).

In some embodiments, R^(A) is 3-methyl-1H-pyrazol-1-yl.

In some embodiments, R^(A) is C₆₋₁₀ aryl optionally substituted by 1, 2,or 3 substituents independently selected from R^(Cy).

In some embodiments, R^(A) is phenyl optionally substituted by 1, 2, or3 substituents independently selected from R^(Cy).

In some embodiments, R^(B) is H.

In some embodiments, R^(B) is Cy², halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3),wherein said C₁₋₆ alkyl and C₂₋₆ alkenyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy²,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, R^(B) is Cy².

In some embodiments, R^(B) is C₆₋₁₀ aryl or 5-10 membered heteroaryl,each of which is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from R^(Cy).

In some embodiments, R^(B) is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3),wherein said C₁₋₆ alkyl and C₂₋₆ alkenyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy²,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, R^(B) is halo.

In some embodiments, R^(C) is H.

In some embodiments, R^(C) is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl and C₂₋₆ alkenyl are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some embodiments, R^(D) is H.

In some embodiments, R^(D) is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl and C₂₋₆ alkenyl are each substituted with 1, 2,3, 4, or 5 substituents independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4).

In some embodiments, the compounds of the invention have Formula IIa:

In some embodiments, the compounds of the invention have Formula IIb:

In some embodiments, the compounds of the invention have Formula IIc:

In some embodiments, the compounds of the invention have Formula IId:

In some embodiments, the compounds of the invention have Formula IIe:

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, L is O.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, L is NR₄.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R³ is H.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R² is CF₃ and R³ is H.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R¹ is H or C₁₋₁₀alkyl.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(A) is Cy¹.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(A) is C₆₋₁₀ aryl or 5-10 memberedheteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(A) is 5-10 membered heteroaryl optionallysubstituted by 1, 2, 3, 4, or 5 substituents independently selected fromR^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(A) is 5 to 6-membered heteroaryloptionally substituted by 1, 2, or 3 substituents independently selectedfrom R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(A) is C₆₋₁₀ aryl optionally substitutedby 1, 2, or 3 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(A) is phenyl optionally substituted by 1,2, or 3 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R¹ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ haloalkyl, CN, OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), whereinsaid C₁₋₆ alkyl and C₂₋₆ alkenyl are each optionally substituted with 1,2, or 3 substituents independently selected from halo, C₁₋₆ haloalkyl,CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(C) is H.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R^(D) is H.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R⁵ is H.

In some embodiments, where the compounds of the invention have FormulaIIa, IIb, IIc, IId, or IIe, R⁶ is H.

In some embodiments, the compounds of the invention have Formula IIIa orIIIb:

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(A) is Cy¹.

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(A) is C₆₋₁₀ aryl or 5-10 membered heteroaryl, each ofwhich is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(A) is 5-10 membered heteroaryl optionally substitutedby 1, 2, 3, 4, or 5 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(A) is 5 to 6-membered heteroaryl optionally substitutedby 1, 2, or 3 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(A) is C₆₋₁₀ aryl optionally substituted by 1, 2, or 3substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(A) is phenyl optionally substituted by 1, 2, or 3substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, CN, OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein saidC₁₋₆ alkyl and C₂₋₆ alkenyl are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, C₁₋₆ haloalkyl, CN,NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(C) is H.

In some embodiments, where the compounds of the invention have FormulaIIIa or IIIb, R^(D) is H.

In some embodiments, the compounds of the invention have Formula IV:

In some embodiments, where the compounds of the invention have FormulaIV, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaIV, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaIV, R^(A) is Cy¹.

In some embodiments, where the compounds of the invention have FormulaIV, R^(A) is C₆₋₁₀ aryl or 5-10 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIV, R^(A) is 5-10 membered heteroaryl optionally substituted by 1, 2, 3,4, or 5 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIV, R^(A) is 5 to 6-membered heteroaryl optionally substituted by 1, 2,or 3 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIV, R^(A) is C₆₋₁₀ aryl optionally substituted by 1, 2, or 3substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIV, R^(A) is phenyl optionally substituted by 1, 2, or 3 substituentsindependently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaIV, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaIV, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl andC₂₋₆ alkenyl are each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3) S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, where the compounds of the invention have FormulaIV, R^(C) is H.

In some embodiments, where the compounds of the invention have FormulaIV, R^(D) is H.

In some embodiments, the compounds of the invention have Formula Va:

In some embodiments, where the compounds of the invention have FormulaVa, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaVa, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaVa, R^(A) is Cy¹.

In some embodiments, where the compounds of the invention have FormulaVa, R^(A) is C₆₋₁₀ aryl or 5-10 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVa, R^(A) is 5-10 membered heteroaryl optionally substituted by 1, 2, 3,4, or 5 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVa, R^(A) is 5 to 6-membered heteroaryl optionally substituted by 1, 2,or 3 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVa, R^(A) is C₆₋₁₀ aryl optionally substituted by 1, 2, or 3substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVa, R^(A) is phenyl optionally substituted by 1, 2, or 3 substituentsindependently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVa, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaVa, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl andC₂₋₆ alkenyl are each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, the compounds of the invention have Formula Vb:

In some embodiments, where the compounds of the invention have FormulaVb, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaVb, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaVb, R^(A) is Cy¹.

In some embodiments, where the compounds of the invention have FormulaVb, R^(A) is C₆₋₁₀ aryl or 5-10 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVb, R^(A) is 5-10 membered heteroaryl optionally substituted by 1, 2, 3,4, or 5 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVb, R^(A) is 5 to 6-membered heteroaryl optionally substituted by 1, 2,or 3 substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVb, R^(A) is C₆₋₁₀ aryl optionally substituted by 1, 2, or 3substituents independently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVb, R^(A) is phenyl optionally substituted by 1, 2, or 3 substituentsindependently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVb, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaVb, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl andC₂₋₆ alkenyl are each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, the compounds of the invention have Formula VI:

In some embodiments, where the compounds of the invention have FormulaVI, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaVI, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaVI, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaVI, Cy² is phenyl optionally substituted by 1, 2, or 3 substituentsindependently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVI, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl andC₂₋₆ alkenyl are each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, where the compounds of the invention have FormulaVI, R^(C) is H.

In some embodiments, where the compounds of the invention have FormulaVI, R^(D) is H.

In some embodiments, the compounds of the invention have Formula VIA:

In some embodiments, where the compounds of the invention have FormulaVIA, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaVIA, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaVIA, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaVIA, Cy² is phenyl optionally substituted by 1, 2, or 3 substituentsindependently selected from R^(Cy).

In some embodiments, where the compounds of the invention have FormulaVIA, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl andC₂₋₆ alkenyl are each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3) NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, the compounds of the invention have Formula VII:

wherein a is 0, 1, 2, or 3.

In some embodiments, where the compounds of the invention have FormulaVII, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaVII, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaVII, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaVII, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl andC₂₋₆ alkenyl are each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3) NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, where the compounds of the invention have FormulaVII, R^(B) is H or halo.

In some embodiments, where the compounds of the invention have FormulaVII, R^(B) is halo.

In some embodiments, where the compounds of the invention have FormulaVII, R^(C) is H.

In some embodiments, where the compounds of the invention have FormulaVII, R^(D) is H.

In some embodiments, where the compounds of the invention have FormulaVII, R^(Cy) is halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, CN, NO₂,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5).

In some embodiments, the compounds of the invention have Formula VIII:

wherein a is 0, 1, 2, or 3.

In some embodiments, where the compounds of the invention have FormulaVIII, R² is CF₃.

In some embodiments, where the compounds of the invention have FormulaVIII, R¹ is H or C₁₋₁₀ alkyl.

In some embodiments, where the compounds of the invention have FormulaVIII, R^(B) is Cy².

In some embodiments, where the compounds of the invention have FormulaVIII, R^(B) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, CN,OR^(a3), C(O)NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl andC₂₋₆ alkenyl are each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c1)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, where the compounds of the invention have FormulaVIII, R^(B) is H or halo.

In some embodiments, where the compounds of the invention have FormulaVIII, R^(B) is halo.

In some embodiments, where the compounds of the invention have FormulaVIII, R^(C) is H.

In some embodiments, where the compounds of the invention have FormulaVIII, R^(D) is H.

In some embodiments, where the compounds of the invention someembodiments have Formula VIII, R^(Cy) is halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, CN, NO₂,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5).

In some embodiments, where the compounds of the invention have FormulaVIII, a is 0.

In some embodiments, the chiral carbon to which —C(O)OR¹ is attached hasan S configuration.

In some embodiments, the carbon to which —R² is attached is chiral andhas an R configuration.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. Thehydrogen atom is formally removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.The term “optionally substituted” means unsubstituted or substituted.The substituents are independently selected, and substitution may be atany chemically accessible position. It is to be understood thatsubstitution at a given atom is limited by valency. Throughout thedefinitions, the term “C_(i-j)” indicates a range which includes theendpoints, wherein i and j are integers and indicate the number ofcarbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example ofa 10-membered cycloalkyl group.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl,or pyridin-4-yl ring.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the term “C_(i-j) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having i to j carbon atoms. Insome embodiments, the alkyl group contains from 1 to 10, 1 to 6, 1 to 4,or from 1 to 3 carbon atoms. Examples of alkyl moieties include, but arenot limited to, chemical groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(i-j) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has i to j carbon atoms. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms or 1 to 4carbon atoms.

As used herein, “C_(i-j) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having i to j carbon atoms. In someembodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbonatoms. Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, the term “C_(i-j) alkylamino” refers to a group offormula —NH(alkyl)₂, wherein the alkyl group has i to j carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “di-C_(i-j)-alkylamino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, i to j carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(i-j) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has i to j carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “C_(i-j) aryl,” employed alone or incombination with other terms, refers to a monocyclic or polycyclic(e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon having i to jring-forming carbon atoms, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. Insome embodiments, aryl is C₆₋₁₀ aryl. In some embodiments, the arylgroup is a naphthalene ring or phenyl ring. In some embodiments, thearyl group is phenyl.

As used herein, the term “arylalkyl” refers to a group of formula—C_(i-j) alkyl-(C_(i-j) aryl). In some embodiments, arylalkyl is C₆₋₁₀aryl-C₁₋₃ alkyl. In some embodiments, arylalkyl is C₆₋₁₀ aryl-C₁₋₄alkyl. In some embodiments, arylalkyl is benzyl.

As used herein, the term “carbonyl,” employed alone or in combinationwith other terms, refers to a —C(═O)— group.

As used herein, the term “carboxy” refers to a group of formula—C(═O)OH.

As used herein, the term “C_(i-j) cycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, which mayoptionally contain one or more alkenylene groups as part of the ringstructure. Cycloalkyl groups can include mono- or polycyclic (e.g.,having 2, 3 or 4 fused rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings (aryl or heteroaryl) fused to the cycloalkyl ring, for example,benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane,and the like. Where the cycloalkyl group includes a fused aromatic ring,the cycloalkyl group can be attached at either an atom in the aromaticor non-aromatic portion. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C₃₋₁₀ or C₃₋₇ cycloalkyl, which can bemonocyclic or polycyclic. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, adamantanyl and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl” refers to a group of formula—C_(i-j) alkyl-(C_(i-j) cycloalkyl). In some embodiments,cycloalkylalkyl is C₃₋₇ cycloalkyl-C₁₋₃ alkyl, wherein the cycloalkylportion is monocyclic. In some embodiments, cycloalkylalkyl is C₃₋₇cycloalkyl-C₁₋₄ alkyl.

As used herein, “C_(i-j) haloalkoxy” refers to a group of formula—O-haloalkyl having i to j carbon atoms. An example haloalkoxy group isOCF₃. An additional example haloalkoxy group is OCHF₂. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “halo” refers to a halogen atom selected fromF, Cl, I or Br. In some embodiments, “halo” refers to a halogen atomselected from F, Cl, or Br. In some embodiments, the halo group is F.

As used herein, the term “C_(i-j) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has i to j carbon atoms. In some embodiments, the haloalkylgroup is fluoromethyl, difluoromethyl, or trifluoromethyl. In someembodiments, the haloalkyl group is trifluoromethyl. In someembodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic moiety, having one or more heteroatom ringmembers selected from nitrogen, sulfur and oxygen. In some embodiments,the heteroaryl group is a 5- to 10-membered heteroaryl ring, which ismonocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl group is a 5- to 6-membered heteroaryl ring,which is monocyclic and which has 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. When theheteroaryl group contains more than one heteroatom ring member, theheteroatoms may be the same or different. The nitrogen atoms in thering(s) of the heteroaryl group can be oxidized to form N-oxides.Example heteroaryl groups include, but are not limited to, pyridine,pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole,thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole,benzothiophene, benzofuran, benzisoxazole, imidazo[1,2-b]thiazole,purine, and the like.

A 5-membered heteroaryl is a heteroaryl group having five ring-formingatoms comprising carbon and one or more (e.g., 1, 2, or 3) ring atomsindependently selected from N, O, and S. Example five-memberedheteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered heteroaryl is a heteroaryl group having six ring-formingatoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Example six-memberedheteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl andpyridazinyl.

As used herein, the term “heteroarylalkyl” refers to a group of formulaC_(i-j) alkyl-(heteroaryl). In some embodiments, heteroarylalkyl 5-10membered heteteroaryl-C₁₋₄ alkyl, wherein the heteroaryl portion ismonocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroarylalkyl is 5-6 membered heteteroaryl-C₁₋₃alkylor 5-6 membered heteteroaryl-C₁₋₄ alkyl, wherein the heteroaryl portionis monocyclic and has 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which optionally contains one or more alkenylene groups as partof the ring structure, and which has at least one heteroatom ring memberindependently selected from nitrogen, sulfur and oxygen. When theheterocycloalkyl groups contains more than one heteroatom, theheteroatoms may be the same or different. Heterocycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ringsystems, including spiro systems. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings (arylor heteroaryl) fused to the non-aromatic ring, for example,1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like. Where theheterocycloalkyl group includes a fused aromatic ring, theheterocycloalkyl group can be attached at either an atom in the aromaticor non-aromatic portion. The carbon atoms or heteroatoms in the ring(s)of the heterocycloalkyl group can be oxidized (e.g. have one or two oxosubstituents) to form a carbonyl, or sulfonyl group (or other oxidizedlinkage) or a nitrogen atom can be quaternized. In some embodiments, theheterocycloalkyl group is 5- to 10-membered, which can be monocyclic orbicyclic and which has 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heterocycloalkyl group is 5- to 6-membered or 5- to7-membered. Examples of heterocycloalkyl groups include 1, 2, 3,4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, andpyran. Further examples of heterocycloalkyl groups include2-oxotetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl,1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, and 2-oxo-1,3-dioxolan-4-yl.

As used herein, the term “heterocycloalkylalkyl” refers to a group offormula alkyl-(heterocycloalkyl). In some embodiments,heterocycloalkylalkyl is 5-10 membered heterocycloalkyl-C₁₋₃ alkyl or5-10 membered heterocycloalkyl-C₁₋₄ alkyl, wherein the heterocycloalkylportion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. In someembodiments, heterocycloalkylalkyl is 5-6 membered heterocycloalkyl-C₁₋₄alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2,3, or 4 heteroatom ring members independently selected from nitrogen,sulfur and oxygen.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention may be isolated as a mixture ofisomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention can also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term “compound,” as used herein, is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified. Compounds herein identified by name orstructure without specifying the particular configuration of astereocenter are meant to encompass all the possible configurations atthe stereocenter. For example, if a particular stereocenter in acompound of the invention could be R or S, but the name or structure ofthe compound does not designate which it is, than the stereocenter canbe either R or S.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, EtOAc,alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (CH₃CN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).

The below Table is a key to some abbreviations used throughout.

Abbreviations

atm atmosphere

BOC tert-butyl-oxy-carbonyl

CAS# Chemical Abstract Service registry number

CBS Corey-Bakshi-Shibata (catalyst)

CH₃CN Acetonitrile

CBZ Carbobenzyloxy

DIPEA N,N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DME dimethylether

DMF dimethyl formamide

dppf 1,1′-bis(diphenylphosphino)ferrocene

EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

ee enantiomeric excess

EtOAc ethyl acetate

h hour(s)

min minute(s)

HOAT 1-hydroxy-7-azabenzotriazole

HOAc acetic acid

HPLC high-performance liquid chromatography

KOAc potassium acetate

LAH lithium aluminum hydride

LDA lithium diisopropylamide

mCPBA 3-meta-chloroperoxybenzoic acid

MeOH Methanol

MS mass spectrometry

MTBE methyl t-butyl ether

NH₄OH ammonium hydroxide

NMP 1-methyl-2-pyrrolidone

PAH pulmonary arterial hypertension

PE petroleum ether

PheOH phenylalanine hydroxylase

Prep-TLC preparative thin-layer chromatography

p-TSA para-toluene sulfonic acid

RT room temperature

SNAr nucleophilic aromatic substitution

TBAF tetrabutylammonium fluoride

tBuOH test-butanol

TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

TEA Triethylamine

TFA trifluoroacetic acid

TH tyrosine hydroxylase

THF Tetrahydrofuran

TLC thin-layer chromatography

TMS Trimethylsilyl

TMSI Trimethylsilyl iodide

TPH tryptophan hydroxylase

Synthesis

Procedures for making compounds described herein are provided below withreference to Schemes 1-10. Optimum reaction conditions and reactiontimes may vary depending on the particular reactants used. Unlessotherwise specified, solvents, temperatures, pressures and otherreaction conditions are readily selected by one of ordinary skill in theart. Specific procedures are provided in the Examples section. Compoundsare named using the “structure to name” function included in ChemDraw®v.12 (Perkin-Elmer).

Typically, reaction progress may be monitored by thin layerchromatography (TLC) or HPLC-MS if desired. Intermediates and productsmay be purified by chromatography on silica gel, recrystallization, HPLCand/or reverse phase HPLC. In the reactions described below, it may benecessary to protect reactive functional groups (such as hydroxy, amino,thio, or carboxy groups) to avoid their unwanted participation in thereactions. The incorporation of such groups, and the methods required tointroduce and remove them are known to those skilled in the art (forexample, see Greene, Wuts, Protective Groups in Organic Synthesis. 2ndEd. (1999)). One or more deprotection steps in the synthetic schemes maybe required to ultimately afford compounds of Formula I. The protectinggroups depicted in the schemes are used as examples, and may be replacedby other compatible alternative groups. Starting materials used in thefollowing schemes can be purchased or prepared by methods described inthe chemical literature, or by adaptations thereof, using methods knownby those skilled in the art. The order in which the steps are performedcan vary depending on the protecting or functional groups introduced andthe reagents and reaction conditions used, but would be apparent tothose skilled in the art.

Compounds of Formula I can be prepared as shown in general in Scheme 1.Briefly, in step 1, an alcohol (where the ring substituted by R^(A),R^(B), R^(C), R^(D) corresponds to ring A of Formula I) (see, e.g.,Intermediate 1) in dioxane is treated with a dichloro heterocycle (e.g.,2-amino-4,6-dichloropyrimidine) in the presence of a base (e.g.,Cs₂CO₃), and heated for several hours (e.g. 12-24 h) at reflux. In step2, a spirocycle of formula B (e.g., (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate) is added to a solution ofcompound A in a solvent (e.g., dioxane) in the presense of a base (e.g.Na₂CO₃), and heated to reflux to provide a compound of formula C. Instep 3, the amino protecting group (P) (e.g. CBZ or BOC) of a compoundof formula C is removed (e.g. with TMSI, transition metal-catalyzedhydrogenation, or strong acid depending on the nature of the protectinggroup). In step 4, a compound of formula D is obtained by esterhydrolysis (e.g. with LiOH in aqueous THF). In some instances, thesequence of steps 3 and 4 can be reversed.

Alcohols (e.g., Intermediate 1) used in Scheme 1 can be prepared asshown in Scheme 2. Briefly, in step 1, to a solution of base (e.g.potassium t-butoxide) in a solvent (e.g. DMSO) is added 3-methylpyrazole and an aryl bromide E (e.g., 1,4-dibromo-2-fluorobenzene), andthe mixture is heated for several hours (e.g. 12-24 h) to provide acompound of formula F. In step 2, a compound of formula F is treatedwith a Grignard reagent (e.g., i-PrMgCl) in a solvent (e.g., THF), thenreacted with ethyl trifluoroacetate in a solvent (e.g., THF) to providea ketone of formula G.

Alternatively, a ketone of formula G can be obtained by treating first afluoro aromatic compound of formula E1 with a strong base (e.g., LDA),then trapping the intermediate aryl lithium with trifluoroacetic acidethyl ester to give a compound of formula F1 (Step 1a). In a subsequentstep 2a, 3-methyl pyrazole can be introduced onto a ketone of formula F1via an SNAr reaction in the presence of base (e.g., K₂CO₃) under solventreflux (e.g., toluene). In step 3, a ketone of formula G is convertedstereospecifically into a chiral alcohol of formula H via either chiraltransfer hydrogenation (e.g., with potassium formate) in the presence ofa transition metal catalyst (e.g., pentamethyl cyclopentadienyl iridium(III) chloride dimer) and a chiral ligand (e.g.,(1R,2R)-(−)-N-(4-toluene sulfonyl)-1,2-diphenyl ethylene diamine) in asolvent (e.g., acetonitrile), or alternatively with a borane reagent(e.g. catechol borane) and a chiral catalyst (e.g. (S)-2-methyl-CBSoxazaborolidine) in a solvent (e.g., THF). Alternatively, an alcohol offormula K can be made in a similar fashion starting from a ketone offormula J (step 2c). A ketone of formula J can be prepared in one step(step 2c) by reacting the aryl ester of formula E2 with a nucleophilicsilylating agent (e.g., trimethyl(trifluoromethyl)silane) in thepresence of a fluoride source (e.g., TBAF) in an inert solvent (e.g.,THF).

Other types of oxygen or nitrogen linker groups (L-groups) can beinstalled as shown in Scheme 3. Briefly, in step 1, to a spirocycliccompound of B (e.g., (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate) in dioxane is added adi-halo heterocycle (e.g., 2-amino-4,6-dichloropyrimidine) in thepresence of a base (e.g., Cs₂CO₃) under solvent reflux (e.g., dioxane)to provide a compound of formula M. In step 2, to a compound of formulaM in a solvent (e.g., dioxane) is added an alcohol or an amine offormula O (e.g., Intermediate 7 or 16) in the presence of a base (e.g.,Cs₂CO₃). After heating at reflux for several hours (e.g., 12-24 h), acompound of formula P is obtained. In step 3, the amino protecting group(P) (e.g., CBZ or BOC) of a compound of formula P is removed (e.g., withTMSI, transition metal-catalyzed hydrogenation, or acid). Then, in step4, a compound of formula Q is obtained by ester hydrolysis (e.g., withLiOH in aqueous THF). In some instances, the sequence of steps 3 and 4can be reversed.

For certain substituents and substitution patterns, palladium-mediatedcoupling reactions (e.g., Suzuki or Stille reactions) can be used, asshown in Schemes 4a, 4b, and 4c. Briefly, in step 1, to a compound offormula R in a solvent (e.g., aqueous dioxane) is added a boronic acidor boronate (e.g., phenyl boronic acid) in the presence of a palladiumcatalyst (e.g., PdCl₂(dppf)-CH₂Cl₂) and a base (e.g., KHCO₃), and themixture heated to reflux for several hours (e.g., 12-24) to provide acompound of formula S. In step 3, the amino protecting group (P) (e.g.,CBZ or BOC) of a compound of formula S is removed (e.g., with TMSI,transition metal-catalyzed hydrogenation, or acid). Then, in step 4, acompound of formula T is obtained by ester hydrolysis (e.g., with LiOHin aqueous THF). In some instances, the sequence of steps 2 and 3 can bereversed. A similar set of conditions can be used when starting with acompound of formula U or X, to obtain a compound of formula W or AA,respectively (Schemes 4b and 4c).

Various substitutions of the central 6-membered ring (e.g., the ringcontaining W, X, and Y) can be accomplished as shown in Scheme 5.Briefly, in step 1, to a solution of a methyl sulfide of formula AB inan inert solvent (e.g., CH₂Cl₂) is added an oxidant (e.g., m-CPBA). Thesolution is stirred at RT for several hours (e.g., 12-24 h) to provide asulfone of formula AC. In step 2, to a solution of a compound of formulaAC in a solvent (e.g., dioxane) is added a spirocyclic compound offormula B (e.g., (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate) in the presence of a base(e.g., Cs₂CO₃), and the mixture is heated for several hours (e.g., 12-24h) to provide a sulfone of formula AD. In step 3, the ester group issaponified (e.g., with LiOH) in an aqueous or alcoholic solvent (e.g.,aqueous THF) to provide an acid of formula AE. In step 4, heating anacid of formula AE in the presence of an alcohol or an amine (e.g.,phenol) and a base (e.g., Cs₂CO₃) for several hours (e.g., 16-24 h) in asolvent (e.g., dioxane), followed in step 5 by deprotection of the amine(e.g. with TMSI, transition metal-catalyzed hydrogenation, or acid)provides a compound of formula AF.

Ester group substituents can be introduced by the general method ofScheme 6. Briefly, in step 1, to a solution of an acid of formula AG inan inert solvent (e.g., CH₂Cl₂) is added a coupling reagent (e.g., EDCIand DMAP), followed by an alcohol (e.g., propanol) to provide a compoundof formula AR In step 2, the benzyl groups of the benzyl ester and ofthe N-CBZ group can be removed with reagents such as TMSI or bytransition metal-catalyzed hydrogenation (e.g., H₂ with Pd/C), affordinga compound of formula AI. In case the amino protecting group is a BOC,an additional step 3, involving treatment with a strong acid (e.g.,TFA), can be used for the final deprotection.

Ethyl esters can be generally prepared according to Scheme 7. Briefly,deprotection of the amino group in a compound of formula AJ, can beaccomplished either with the use of a dealkylating agent (e.g., TMSI) orvia transition metal-catalyzed hydrogenation (e.g., H₂ with Pd/C) if theprotecting group is CBZ, or with a strong acid (e.g., TFA or HCl), ifthe protecting group is BOC, to provide AK. It will be recognized bythose skilled in the art that many other protecting groups can be usedalternatively (for example, see Greene, Wuts, Protective Groups inOrganic Synthesis. 2nd Ed. (1999)).

Various esters can be made via direct alcohol coupling to the acid, asshown in Scheme 8, or via alkylation of the acid, as shown in Scheme 9.Briefly, an amino acid of formula AL is dissolved in an alcoholicsolvent (e.g., n-octanol), optionally in the presence of a co-solvent(e.g., toluene), and heated in the presence of acid (e.g., p-TSA) forseveral hours (e.g., 12-24 h), optionally in the presence of a watertrapping material (e.g., molecular sieve) or apparatus (e.g., Dean-Starktrap) to produce an ester of formula AM. Alternatively, in step 1, anacid of formula AN is dissolved in a solvent (e.g., DMF) in the presenceof a base (e.g., K₂CO₃) and treated with an alkyl halide (e.g.,2-chloro-ethyl-dimethyl-amine). After heating the solution for severalhours (e.g., 12-24 h), an ester of formula AO is obtained. In step 2,removal of the amino protecting group (e.g., with an acid like TFA in aninert solvent such as CH₂Cl₂ in case of a BOC protecting group) providesan ester of formula AP. Other compatible deprotection methods apparentto those skilled in the art can be applied for other types of aminoprotecting groups.

t-Butyl esters can be made via direct alcohol coupling to the acid, asshown in Scheme 10. Briefly, in step 1, an acid of formula AQ isdissolved in a solvent (e.g., DMF) in the presence of t-butanol, andtreated with a coupling agent (e.g., EDCI and DMAP) to provide acompound of formula AR. In step 2, removal of the amino protecting groupis achieved as described earlier to afford a compound of formula AS.

Methods of Use

The compounds of the invention can be used to inhibit the activity ofthe TPH1 enzyme in a cell by contacting the cell with an inhibitingamount of a compound of the invention. The cell can be part of thetissue of a living organism, or can be in culture, or isolated from aliving organism. Additionally, the compounds of the invention can beused to inhibit the activity of the TPH1 enzyme in an animal,individual, or patient, by administering an inhibiting amount of acompound of the invention to the cell, animal, individual, or patient.

Compounds of the invention can also lower peripheral serotonin levels inan animal, individual, or patient, by administering an effective amountof a compound of the invention to the animal, individual, or patient. Insome embodiments, the compounds of the invention can lower levels ofperipheral serotonin (e.g., 5-HT in the GI tract) selectively overnon-peripheral serotonin (e.g., 5-HT in the CNS). In some embodiments,the selectivity is 2-fold or more, 3-fold or more, 5-fold or more,10-fold or more, 50-fold or more, or 100-fold or more.

As TPH1 inhibitors that can lower peripheral serotonin levels, thecompounds of the invention are useful in the treatment and prevention ofvarious diseases associated with abnormal expression or activity of theTPH1 enzyme, or diseases associated with elevated or abnormal peripheralserotonin levels. In some embodiments, the treatment or preventionincludes administering to a patient in need thereof a therapeuticallyeffective amount of a TPH1 inhibitor of the invention.

Biological assays, some of which are described herein, can be used todetermine the inhibitory effect of compounds against TPH (such as TPH1)in vitro and/or in vivo. In vitro biochemical assays for human, mouse,and rat TPH1 and human TPH2, PheOH, and TH may be used to measureinhibition of enzyme activity and the selectivity among TPH1, TPH2,PheOH, and TH. In addition, the efficacy of these compounds can bedetermined, for example, by measuring their effect on intestinal 5-HTlevels in rodents after oral administration.

Diseases treatable or preventable by administering a TPH1 inhibitor ofthe invention include bone disease such as, for example, osteoporosis,osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia,renal osteodystrophy, Paget's disease, fractures, and bone metastasis.In some embodiments, the disease is osteoporosis, such as primary type 1(e.g., postmenopausal osteoporosis), primary type 2 (e.g., senileosteoporosis), and secondary (e.g., steroid- or glucocorticoid-inducedosteoporosis).

The present invention further includes methods of treating or preventingbone fracture such as, for example, osteoporotic or traumatic fracture,or surgical fractures associated with an orthopedic procedure (e.g.,limb lengthening, bunion removal, an increase in bone formationassociated with a prosthesis, bone metastasis, or spinal fusion).

Further diseases treatable or preventable by the methods of theinvention include cardiovascular diseases such as atherosclerosis andpulmonary hypertension (PH), including idiopathic or familial PH, andalso including PH associated with or brought on by other diseases orconditions. In some embodiments, the PH disease is pulmonary arterialhypertension (PAH).

The types of PAH treatable according to the methods of the inventioninclude (1) idiopathic (IPAH), (2) familial (FPAH), and (3) associated(APAH) which is the most common type of PAH. The latter is PAH which isassociated with other medical conditions including, for example, (1)collagen vascular disease (or connective tissue disease) which includeautoimmune diseases such as scleroderma or lupus; (2) congenital heartand lung disease; (3) portal hypertension (e.g., resulting from liverdisease); (4) HIV infection; (5) drugs (e.g., appetite suppressants,cocaine, and amphetamines; (6) other conditions including thyroiddisorders, glycogen storage disease, Gaucher disease, hereditaryhemorrhagic telangiectasia, hemoglobinopathies, myeloproliferativedisorders, and splenectomy. APAH can also be PAH associated withabnormal narrowing in the pulmonary veins and/or capillaries such as inpulmonary veno-occlusive disease (PVOD) and pulmonary capillaryhemangiomatosis. Another type of PAH is associatead with persistentpulmonary hypertension of the newborn (PPHN).

Further diseases treatable or preventable by the methods of theinvention include metabolic diseases such as diabetes andhyperlipidemia; pulmonary diseases such as chronic obstructive pulmonarydisease (COPD), and pulmonary embolism; gastrointestinal diseases suchas IBD, colitis, chemotherapy-induced emesis, diarrhea, carcinoidsyndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia,constipation, lactose intolerance, MEN types I and II, Ogilvie'ssyndrome, pancreatic cholera syndrome, pancreatic insufficiency,pheochromacytoma, scleroderma, somatization disorder, Zollinger-EllisonSyndrome, or other gastrointestinal inflammatory conditions; liverdiseases such as chronic liver disease; cancers such as liver cancer,breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer,neuroendocrine tumors, pancreatic cancer, prostate cancer, and bonecancer (e.g., osteosarcoma, chrondrosarcoma, Ewings sarcoma,osteoblastoma, osteoid osteoma, osteochondroma, enchondroma,chondromyxoid fibroma, aneurysmal bone cyst, unicameral bone cyst, giantcell tumor, and bone tumors); blood diseases (e.g., myeoloproliferativesyndrome, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin'slymphoma, myeloma, and anemia such as aplastic anemia and anemiaassociated with kidney disease; and blood cancers (e.g., leukemias suchas acute lymphocytic leukemia (ALL), chronic lymphocytic leukemica(CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia(CML)).

The compounds of the invention are also useful in the treatment andprevention of serotonin syndrome.

In some embodiments, the present invention includes methods of loweringplasma cholesterol, lowering plasma triglycerides, lowering plasmaglycerol, lowering plasma free fatty acids in a patient by administeringto said patient a therapeutically effective amount of a compound of theinvention.

The compounds of the invention are also useful in the treatment andprevention of inflammatory disease, such as allergic airway inflammation(e.g., asthma).

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the enzyme with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having the TPH1 enzyme, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the TPH1enzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)inhibiting the disease; for example, inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),or 2) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology).

As used herein the term “preventing” or “prevention” refers toinhibiting onset or worsening of the disease; for example, in anindividual who may be predisposed to the disease, condition or disorderbut does not yet experience or display the pathology or symptomatologyof the disease.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods can beused in combination with the compounds of the present invention fortreatment or prevention of various diseases, disorders or conditionsdisclosed herein. The agents can be combined with the present compoundsin a single dosage form, or the agents can be administeredsimultaneously or sequentially in separate dosage forms.

Example pharmaceutical agents that may be useful in a combinationtherapy for blood disorders like blood cancers include parathyroidhormone, anti-sclerostin antibodies, kathepsin K inhibitors, andanti-Dickopff 1.

Example pharmaceutical agents that may be useful in a combinationtherapy for cancer include leuprolide, goserelin, buserelin, flutamide,nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine,doxorubicin, etoposide, vinblastine, paclitaxel, carboplatin, andvinorelbine. Therapies that can be combined with TPH inhibition includeradiation therapy, high-intensity focused ultrasound, or surgery (e.g.,removal of diseased tissues). Other drugs for use in treating cancerinclude testolactone, anastrozole, letrozole, exemestane, vorozole,formestane, fadrozole, GnRH-analogues, temozolomide, bavituximab,cyclophosphamide, fluorouracil, fulvestrant, gefitinib, trastuzumab,IGF-1 antibodies, lapatinib, methotrexate, olaparib, BSI-201, pazopanib,rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel,vatalinib, bevacizumab, and octreotide.

Example pharmaceutical agents that may be useful in combination therapyfor cardiovascular or pulmonary diseases include endothelin receptorantagonists such as ambrisentan, BMS-193884, bosentan, darusentan,SB-234551, sitaxsentan, tezosentan and macitentan. Anticoagulants suchas warfarin, acenocoumarol, phenprocoumon, phenindione, heparin,fondaparinux, argatroban, bivalirudin, lepirudin, and ximelagatran mayalso be useful in combination therapy. Pharmaceutical agents forcombination therapy further include calcium channel blockers likeamlodipine, felodipine, nicardipine, nifedipine, nimodipine,nisoldipine, nitrendipine, lacidipine, lercanidipine, phenylalkylamines,verapamil, gallopamil, diltiazem, and menthol. Prostacyclins likeepoprostenol, iloprost and treprostinil may also be combined with theTPH inhibitors of the invention. Further pharmaceutical agents forcombination therapy in cardiovascular or pulmonary diseases include PDE5inhibitors like sildenafil, tadalafil, and vardenafil; diuretics likefurosemide, ethacrynic acid, torasemide, bumetanide,hydrochlorothiazide, spironolactone, mannitol, nitric oxide or nitricoxide releasers, and soluble guanylate cyclase stimulators, such asriociguat. Yet further pharmaceutical agents for combination therapyinclude APJ receptor agonists (WO 2013/111110); IP receptor agonists (WO2013/105057; WO 2013/105066; WO 2013/105061; WO 2013/105063; WO2013/105065; WO 2013/105058); and PDGF receptor inhibitors (WO2013/030802).

Example pharmaceutical agents that may be useful in combination therapyfor metabolic disorders include HSL inhibitors such as those disclosedin International Patent Publications WO2006/074957; WO2005/073199;WO2004/11 1031; WO2004/111004; WO2004/035550; WO2003/051841;WO2003/051842; and WO2001/066531.

Example pharmaceutical agents that may be useful in combination therapyfor bone disorders and diseases include bisphosphantes such asetidronate, clodronate, tiludronate, pamidronate, neridronate,olpadronate, alendronate, ibandronate, risedronate, cimadronate,zoledronate, and the like. Serotonin receptor modulators, such as5-HT_(1B), 5-HT_(2A), and 5-HT_(2B) agonists or antagonists, may also beuseful in combination therapy for bone disease. Other useful agents forcombination therapy include selective serotonin reuptake inhibitors(SSRI), anti-serotonin antibodies, and beta blockers such as IPS339,ICII 18,551, butaxamine, metipranolol, nadol, oxprenolol, penbutolol,pindolol, propranolol, timolol, and sotalol. Further useful agents forcombination therapy for the treatment of bone disorders, such asosteoporosis, include teriparatide, strontium ranelate, raloxifene, anddenosumab.

Administration, Pharmaceutical Formulations, Dosage Forms

The compounds of the invention can be administered to patients (animalsand humans) in need of such treatment in appropriate dosages that willprovide prophylactic and/or therapeutic efficacy. The dose required foruse in the treatment or prevention of any particular disease or disorderwill typically vary from patient to patient depending on, for example,particular compound or composition selected, the route ofadministration, the nature of the condition being treated, the age andcondition of the patient, concurrent medication or special diets thenbeing followed by the patient, and other factors. The appropriate dosagecan be determined by the treating physician.

A compound of this invention can be administered orally, subcutaneously,topically, parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Parenteral administrationcan involve subcutaneous injections, intravenous or intramuscularinjections or infusion techniques.

Treatment duration can be as long as deemed necessary by a treatingphysician. The compositions can be administered one to four or moretimes per day. A treatment period can terminate when a desired result,for example a particular therapeutic effect, is achieved. Or a treatmentperiod can be continued indefinitely.

In some embodiments, the pharmaceutical compositions can be prepared assolid dosage forms for oral administration (e.g., capsules, tablets,pills, dragees, powders, granules and the like). A tablet can beprepared by compression or molding. Compressed tablets can include oneor more binders, lubricants, glidants, inert diluents, preservatives,disintegrants, or dispersing agents. Tablets and other solid dosageforms, such as capsules, pills and granules, can include coatings, suchas enteric coatings.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration can include, for example, pharmaceutically acceptableemulsions, microemulsions, solutions, suspensions, syrups and elixirs.Suspensions can include one or more suspending agents

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants.

Compositions and compounds of the present invention can be administeredby aerosol which can be administered, for example, by a sonic nebulizer.

Pharmaceutical compositions of this invention suitable for parenteraladministration include a compound of the invention together with one ormore pharmaceutically acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions. Alternatively, thecomposition can be in the form of a sterile powder which can bereconstituted into a sterile injectable solutions or dispersion justprior to use.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof TPH1 as described below.

EXAMPLES

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials.

¹H NMR Spectra were acquired on one or more of three instruments: (1)Agilent UnityInova 400 MHz spectrometer equipped with a 5 mm AutomationTriple Broadband (ATB) probe (the ATB probe was simultaneously tuned to¹H, ¹⁹F and ¹³C); (2) Agilent UnityInova 500 MHz spectrometer; or (3)Varian Mercury Plus 400 MHz spectrometer. Several NMR probes were usedwith the 500 MHz NMR spectrometer, including both 3 mm and 5 mm ¹H, ¹⁹Fand ¹³C probes and a 3 mm X¹H¹⁹F NMR probe (usually X is tuned to ¹³C).For typical ¹H NMR spectra, the pulse angle was 45 degrees, 8 scans weresummed and the spectral width was 16 ppm (−2 ppm to 14 ppm). Typically,a total of about 32768 complex points were collected during the 5.1second acquisition time, and the recycle delay was set to 1 second.Spectra were collected at 25° C. ¹H NMR Spectra were typically processedwith 0.3 Hz line broadening and zero-filling to about 131072 pointsprior to Fourier transformation. Chemical shifts were expressed in ppmrelative to tetramethylsilane. The following abbreviations are usedherein: br=broad signal, s=singlet, d=doublet, dd=double doublet,ddd=double double doublet, dt=double triplet, t=triplet, td=tripledoublet, tt=triple triplet q=quartet, m=multiplet.

Liquid chromatography-mass spectrometry (LCMS) experiments to determineretention times and associated mass ions were performed using one ormore of the following Methods A, B, and C:

Method A:

Waters BEH C18, 3.0×30 mm, 1.7 μm, was used at a temperature of 50° C.and at a flow rate of 1.5 mL/min, 2 μL injection, mobile phase: (A)water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOHwith 0.1% formic acid; retention time given in minutes. Method Adetails: (I) ran on a Binary Pump G1312B with UV/Vis diode arraydetector G1315C and Agilent 6130 mass spectrometer in positive andnegative ion electrospray mode with UV PDA detection with a gradient of15-95% (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B)(III) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) holdfor 0.29 min at 15% (B);

Method B:

An Agilent Zorbax Bonus RP, 2.1×50 mm, 3.5 μm, was used at a temperatureof 50° C. and at a flow rate of 0.8 mL/min, 2 μL injection, mobilephase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase(B) MeOH with 0.1% formic acid; retention time given in minutes. Methoddetails: (I) ran on a Binary Pump G1312B with UV/Vis diode arraydetector G1315C and Agilent 6130 mass spectrometer in positive andnegative ion electrospray mode with UV-detection at 220 and 254 nm witha gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min lineargradient (IV) hold for 0.29 min at 5% (B).

Method C:

An API 150EX mass spectrometer linked to a Shimadzu LC-10AT LC systemwith a diode array detector was used. The spectrometer had anelectrospray source operating in positive and negative ion mode. LC wascarried out using an Agilent ZORBAX XDB 50×2.1 mm C18 column and a 0.5mL/minute flow rate. Solvent A: 95% water, 5% acetonitrile containing0.01% formic acid; Solvent B: acetonitrile. The gradient was shown asbelow. 0-0.5 min: 2% solvent (B); 0.5-2.5 min: 2% solvent B to 95%solvent (B); 2.5-4.0 min. 95% solvent (B); 4.0-4.2 min: 95% solvent (B)to 2% solvent B; 4.2-6.0 min: 2% solvent (B).

Microwave experiments were carried out using a Biotage Initiator™, whichuses a single-mode resonator and dynamic field tuning. Temperatures from40-250° C. were achieved, and pressures of up to 20 bars were reached.

Preparative HPLC purification was carried out using either aC18-reverse-phase column from Genesis (C18) or a C6-phenyl column fromPhenomenex (C6 Ph) (100×22.5 mm i.d. with 7 micron particle size, UVdetection at 230 or 254 nm, flow 5-15 mL/min), eluting with gradientsfrom 100-0 to 0-100% water/acetonitrile or water/MeOH containing 0.1%formic acid. Fractions containing the required product (identified byLCMS analysis) were pooled, the organic fraction removed by evaporation,and the remaining aqueous fraction lyophilised, to give the product.

Chiral HPLC was carried out using a Chiralpak AD column, 4.4 mm×250 mm,particle size 5 micron

Compounds which required column chromatography were purified manually orfully automatically using either a Biotage SP1™ Flash Purificationsystem with Touch Logic Control™ or a Combiflash Companion® withpre-packed silica gel Isolute® SPE cartridge, Biotage SNAP cartridge orRedisep® Rf cartridge respectively.

Preparation of Alcohols and Amines

The chiral alcohols drawn below are shown in their absoluteconfiguration (unless otherwise shown). Their enantiopurity (% ee) canbe determined via Mosher ester analysis and analyzed as described in theliterature (Dale, J. A. & Mosher, H. S. Nuclear Magnetic ResonanceEnantiomer Regents. Configurational Correlations Via Nuclear MagneticResonance Chemical Shifts Of Diastereomeric Mandelate,O-Methylmandelate, and alpha-Methoxy alpha-Trifluoromethylphenylacetate(MTPA) Esters. J. Am. Chem. Soc. 95, 512-519 (1973)). The chiralalcohols of the invention are preferably enantiomerically enriched, forexample, to >95% ee.

Representative Mosher Ester Preparation

To a solution of(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(46 mg, 0.20 mmol, Intermediate 3) was added pyridine (138 mg, 1.7 mmol)followed by the addition of either (S orR)-α-methoxy-α-trifluoromethyl-phenylacetyl chloride (10 mg, 0.40 mmol).The reaction was stirred for 12 h, then the material was purifieddirectly on silica gel chromatography (EtOAc/heptane) to provide the“Mosher ester” which was analyzed by ¹H NMR for enantiomeric purity.

Intermediate 1:(R)-1-(4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

Step 1:

Potassium t-butoxide (16.3 g, 145 mmol) was dissolved in DMSO (100 mL).To this solution was added 3-methyl pyrazole (10.4 g, 120 mmol) and thereaction was heated at 50° C. for 30 min. 1,4-Dibromo-2-fluorobenzene(31 g, 120 mmol) was then added and the reaction stirred at 50° C. for16 h. The reaction was cooled to RT and extracted with water and EtOAc,washed with brine, dried over Na₂SO₄, and then filtered and concentratedin vacuo. Purification by normal phase silica gel column chromatography(EtOAc/heptane) provided 1-(2,5-dibromophenyl)-3-methyl-1H-pyrazole.

Step 2:

1-(2,5-dibromophenyl)-3-methyl-1H-pyrazole (23.0 g, 73 mmol) from Step 1was dissolved in 200 mL of THF and cooled to 0° C. i-Propyl magnesiumchloride (2.0 M in THF, 40 mL) was added dropwise and the reaction wasstirred for 45 min, then ethyl trifluoroacetate (10.5 mL) was added. Thereaction was stirred for 30 min at 0° C., then 10% HCl is added dropwise(400 mL). The reaction was extracted with water and EtOAc, washed withbrine, dried over Na₂SO₄, filtered, and then concentrated in vacuo.Purification by normal phase silica gel column chromatography(EtOAc/heptane) provided1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone.

Step 3: Method A:

Pentamethylcyclopentadienyl iridium (III) chloride dimer(CAS#12354-84-6) (10.4 mg) and (1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenyl ethylene diamine (CAS#144222-34-4) (9.2 mg) werecombined in water (120 mL), then heated to 50° C. for 5 h to provide the“Iridium complex.”1-[4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone(16 g, 48 mmol) was dissolved in acetonitrile (120 mL) to which theIridium complex and potassium formate (3.1 g, 3.7 mmol) were added. Thereaction mixture was heated to 50° C. for 8 h. The reaction mixture wasthen cooled to RT, partitioned between water and EtOAc, and extracted.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Recrystallization from hot heptane(200 mL) provided the title compound.

Method B:

Alternatively, the trifluoromethyl (or other prochiral) ketones offormula G or L (scheme 2) were asymmetrically reduced as follows (seefor example: Corey, E. J. & Link, J. O. A General, Catalytic, andEnantioselective Synthesis of Alpha-amino Acids. J. Am. Chem. Soc. 114,1906-1908 (1992)): Catechol borane (95 mL, 1 M in THF) and(S)-2-methyl-CBS oxazaborolidine (2.6 g, 9.6 mmol) were mixed in ajacketed glass reactor. The mixture was stirred at RT for 20 min, thenthe jacket was cooled to −78° C. At a reaction temperature of −65° C.,1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone(16 g, 48 mmol) in THF (150 mL) was added dropwise over 2 h. Thereaction was then warmed to −36° C. and held at this temperature for 22h. Then the reaction was quenched with 3 N NaOH (100 mL) whilemaintaining a reaction temperature of <−25° C. The reaction was thenwarmed to 0° C. and H₂O₂ (30%, 100 mL) was added over 30 min, thenwarmed to RT for 4 h. The reaction mixture was quenched with 1 N NaOH,extracted with ether, washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. Purification on normal phase silica gelchromatography (EtOAc/heptane) provided the product as a viscous oil.

Intermediate 2:(R)-1-(5-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

Step 1:

Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) andcooled to −40° C. Then n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4mmol) was added dropwise, and the reaction was stirred at −40° C. for 1h, then cooled to −78° C. A solution of 1-bromo-4-fluorobenzene (5 g,28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at−78° C. for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol)in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0°C. over an hour. The reaction was quenched with NH₄Cl (aq. sat), andextracted with EtOAc, washed with brine, and dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by normal phase silicagel column chromatography (EtOAc/heptane) provided1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone.

Step 2:

1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (2.20 g, 8.12 mmol)from Step 1, K₂CO₃ (1.68 g, 12.2 mmol), and 3-methyl-1H-pyrazole (1.33g, 16.2 mmol) were stirred in toluene (10 mL). The reaction was thenheated to 110° C. for 16 h. The reaction was cooled, and water and EtOAcwere added. The toluene-EtOAc layer is removed in vacuo, and then thereaction is extracted with water and EtOAc, washed with brine, and driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column chromatography (EtOAc/heptane) provided1-[5-bromo-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoroethanone.

Step 3:

The title compound was prepared using the Iridium complex-catalyzedhydrogenation as described for Intermediate 1,(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

Intermediate 3:(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

Step 1:

Potassium t-butoxide (3.9 g, 0.33 mmol) was dissolved in DMSO (25 mL).To this solution was added 3-methyl pyrazole (2.7 g, 0.33 mmol) and thereaction was heated at 50° C. for 30 min.1-Bromo-4-chloro-2-fluorobenzene (4.6 g, 0.22 mmol) was then added andthe reaction was stirred at 50° C. for 16 h. The reaction was cooled toRT and extracted with water and EtOAc, washed with brine, and dried overNa₂SO₄, filtered and concentrated in vacuo. Purification by normal phasesilica gel column chromatography (EtOAc/heptane) provided1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole and1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole as a 4:1 mixture thatwas used in the next step directly.

Step 2:

The mixture from Step 1 (8 g, 0.39 mmol) was dissolved in 160 nil, ofTHF and cooled to 0° C. i-Propyl magnesium chloride (2.0 M in THF, 23mL) was added dropwise and the reaction stirred for 45 min, then ethyltrifluoroacetate (6 mL) was added. The reaction was stirred for 30 minat 0° C., then 10% HCl was added dropwise (40 mL). The reaction wasextracted with water and EtOAc, washed with brine, and dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column chromatography (EtOAc/heptane) provided1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanoneas a white solid.

Step 3:

The title compound was prepared using the Iridium complex-catalyzedhydrogenation, as described for Intermediate 1(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

Intermediate 4:(R)-1-(5-chloro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)pyrrolidin-2-one

To a solution of (R)-1-(4)-2,2,2-trifluoroethanol (300 mg, 1.04 mmol) intoluene (7 mL) was added pyrrolidin-2-one (89 mg, 1.04 mmol),(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (74 mg, 0.52 mmol), CuI(50 mg, 0.26 mmol) and K₂CO₃ (360 mg, 2.6 mmol). The reaction was heatedin a sealed tube to 130° C. for 12 h and then cooled to RT. The solidswere filtered and the product was purified by normal phase silica gelchromatography (EtOAc:petroleum ether) to to provide the title compoundas a white solid.

Intermediate 5:(R)-2,2,2-Trifluoro-1-(2-methyl-1H-benzo[d]imidazol-4-yl)ethanol

Step 1:

4-Bromo-2-methyl-1H-benzimidazole (500 mg, 2.37 mmol) was dissolved inTHF (8 mL) and cooled to −78° C. n-Butyllithium (2.3 mL, 2.5 Minhexanes, 5.7 mmol) was added dropwise and the reaction was stirred at−78° C. for 30 min. Trifluoroacetic acid ethyl ester (339 μL, 2.8 mmol)was added and the reaction was stirred at 0° C. for 1 h. The reactionwas quenched with HCl (2 N, 4 mL), then extracted with water and EtOAc,washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by normal phase silica gel column chromatography(CH₂Cl₂/MeOH/NH₄OH) provided2,2,2-trifluoro-1-(2-methyl-1H-benzoimidazol-4-yl)-ethanone.

Step 2:

The title compound was prepared using the Iridium complex-catalyzedhydrogenation, as described for Intermediate 1(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

Intermediate 6: 1-(4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethanol

Step 1:

1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazolemixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved inTHF (6 mL) and cooled to 0° C. i-Propyl magnesium chloride (2.76 mL, 2.0M in THF, 5.52 mmol) was added dropwise and allowed to warm to RT over30 min. The reaction was then cooled to −15° C. Acetyl chloride (481 μL,5.5 mmol) was added and the reaction was warmed to RT for 3 h. Thereaction was quenched with HCl (2 N, 4 mL), then extracted with waterand EtOAc, washed with brine, and dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by normal phase silica gel columnchromatography (EtOAc/heptane) provided1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanone.

Step 2:

1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanone (400 mg, 1.70mmol) from Step 1 was dissolved in MeOH (10 mL) and cooled to 0° C.NaBH₄ (129 mg, 3.41 mmol) was added portionwise, then the reaction waswarmed to RT, stirred for 30 min, then quenched with acetone. The MeOHwas removed in vacuo then the residue was partitioned between water andEtOAc and extracted several times. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by normal phase silica gel column chromatography(CH₂Cl₂/MeOH/NH₄OH) provided the title compound.

Intermediate 7: 1-(2,6-dibromophenyl)ethanol

To a solution of 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanone(CAS#1208078-23-2) (3 g, 9 mmol) in EtOH (50 mL) was added NaBH₄ (340mg, 9 mmol) at 5° C. The reaction was warmed to RT for 1 h, thenextracted with EtOAc NaHCO₃, brine, and dried over Na₂SO₄ filtered andconcentrated in vacuo to provide1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol as a light yellow oil.

Intermediate 8: 1-(2,5-dibromophenyl)ethanol

This compound was made as described above for Intermediate 7,1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol, starting with1-(2,5-dibromophenyl)-2,2,2-trifluoroethanone to provide a light yellowoil.

Intermediate 9: (4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanol

Step 1:

1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazolemixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved inTHF (6 mL) then cooled to 0° C. i-Propyl magnesium chloride (2.76 mL,2.0 M in THF, 5.52 mmol) was added dropwise and the reaction was warmedto RT for 30 min. The reaction was then cooled to −15° C. andparaformaldehyde (166 mg, 5.5 mmol) was added. The reaction mixture wasallowed to warm to RT and stirred for 1 h. DMF (500 mL) was added andthe reaction was stirred for an additional 1 h. The reaction wasquenched with HCl (2 N, 4 mL), diluted with water, extracted with EtOAc,washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by normal phase silica gel column chromatography(EtOAc/heptane) provided4-chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde.

Step 2:

4-Chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde (446 mg, 2.03 mmol) fromStep 1 was dissolved in MeOH (14 mL) and cooled to 0° C. NaBH₄ (175 mg,4.61 mmol)) was added portionwise. The reaction mixture was allowed towarm to RT, and after 90 min was quenched with acetone. The MeOH wasremoved in vacuo. The residue was partitioned between water and EtOAcand then extracted. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification bynormal phase silica gel column chromatography (EtOAc/heptane) providedthe title compound.

Using the procedure described for Intermediate 3,(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol,the following alcohols (Intermediates 10-15) shown in the Table belowwere prepared starting with the appropriately substituted1-bromo-2-fluorobenzene.

LCMS No. Name Structure (MH+) Intermediate 10(R)-2,2,2-trifluoro-1-(4-methyl-2-(3- methyl-1H-pyrazol-1-yl)phenyl)ethanol

271 Intermediate 11 (R)-2,2,2-trifluoro-1-(4-methoxy-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethanol

287 Intermediate 12 (R)-1-(3-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethanol

291 Intermediate 13 (R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(trifluoromethyl) phenyl)ethanol

325 Intermediate 14 (R)-2,2,2-trifluoro-1-(4-fluoro-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethanol

274 Intermediate 15 (R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3- yl)ethanol

272

Intermediate 16: (2-Phenoxy-6-(piperidin-1-yl)phenyl)methanamine

Step 1:

To a solution of phenol (415 mg, 4.5 mmol) in 60 mL of DMF was added NaH(60%, 6.0 mmol) at 0° C. The reaction was stirred for 1 h, then2-fluoro-6-(piperidin-1-yl)benzonitrile (CAS#646989-68-6) (612 mg, 3.0mmol) was added and the reaction stirred for 48 h at RT. The reactionmixture was then diluted with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄, thenconcentrated in vacuo. Purification by normal phase silica gel columnchromatography (EtOAc/heptane) provided2-phenoxy-6-(piperidin-1-yl)benzonitrile as an off-white solid.

Step 2:

To 2-phenoxy-6-(piperidin-1-yl)benzonitrile (250 mg, 0.9 mmol) from Step1 in 20 mL of MeOH was added Raney Nickel (5%) and NH₄OH (2 mL). Thereaction was stirred under 1 atm of H₂ at RT for 2 h. The solid wasfiltered away and the filtrate was concentrated in vacuo to provide thetitle compound as a viscous oil.

Intermediate 17:(R)-1-(4-Chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol

Step 1:

1-Bromo-4-chloro-2-(2-methoxy-ethoxy)-benzene (CAS#1245563-20-5) (5.00g, 18.8 mmol) was dissolved in THF (30 mL) and cooled to 0° C.i-Propylmagnesium bromide (11.3 mL, 2.0 M in THF, 22.6 mmol) was addeddropwise, and the reaction was stirred at 10° C. for 30 min, then warmedto RT for 16 h. The reaction was then cooled to −15° C. andtrifluoroacetic acid ethyl ester (3.37 mL, 28.2 mmol) was added. Thereaction was stirred at 10° C. for 1 h. The reaction was quenched withHCl (2 N, 38 mL) at 0° C. The reaction mixture was diluted with waterand extracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, then concentrated in vacuo. Purification bynormal phase silica gel column chromatography (EtOAc/heptane) provided1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanone.

Step 2:

The title compound was prepared using the Iridium complex-catalyzedhydrogenation as described for Intermediate 1(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

Intermediate 18:(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol

To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol(300 mg, 1.1 mmol) in dioxane (12 mL) was added phenyl boronic acid (185mg, 1.5 mmol), Pd₂(dppf)Cl₂ (35 mg, 0.07 mmol) and Na₂CO₃ (3 mL, 2.0 M,aq). The reaction was heated to 90° C. for 2 h, then cooled to RT, andconcentrated in vacuo. The residue was taken up in CH₂Cl₂, washed withbrine, and extracted with CH₂Cl₂. The combined organic layers were driedover Na₂SO₄. Purification by normal phase silica gel column(EtOAc/hexanes) to provide a white solid.

Intermediate 19:(R)-1-(4-chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2,2-trifluoroethanol

This compound was made in the same way as described for Intermediate 18(R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol to providea white solid.

Intermediate 20:(R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanol

Step 1:

To the solution of 2-chloro-6-methylnicotinic acid (5 g, 29.1 mmol) inCH₂Cl₂ (40 mL) was added oxalyl dichloride (8.1 g, 63.8 mmol) at 0° C.and the reaction mixture was stirred for 2 h. The mixture wasconcentrated and 40 mL of methanol was then added at 0° C. and thereaction mixture was stirred at RT for 12 h. The mixture was thenconcentrated in vacuo and extracted with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide methyl 2-chloro-6-methylnicotinate thatis used without further purification as a light yellow solid.

Step 2:

To a solution of 3-methyl-1H-pyrazole (1.1 g, 13.4 mmol) in DMF (5 ml)was added sodium hydride (1.0 g, 60% in oil) at 0° C. The reactionmixture was stirred for 1 h at 0° C. and then. A solution of methyl2-chloro-6-methylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was addeddropwise to the reaction mixture at 0° C. After addition, the mixturewas heated to 80° C. and stirred for 12 h. After this time, the mixturewas poured into ice-water and extracted and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo and then purified by normal phasesilica gel column (EtOAc/hepate) to provide methyl6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate as a brown semi-solid.

Step 3:

To a solution of methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate(3.7 g, 16 mmol) and trimethyl(trifluoromethyl)silane (11.4 g, 80.2mmol) in toluene (60 ml), was added dropwise at −78° C. and then thesolution of tetrabutyl ammonium fluoride (1.6 mL, 1.0 M in THF) wasadded dropwise to the reaction mixture at −78° C. After addition, themixture was warmed slowly up to RT and stirred for 12 h. The reactionmixture was concentrated and the resulting residue was dissolved inmethanol (30 mL) 6 N HCl (30 mL) was added to the reaction mixture andthe resulting mixture was stirred for 2 h. The reaction mixture wasconcentrated, adjusted to pH 6 with sat.NaHCO₃ and extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo and purified by normal phase silicagel column (EtOAc/hepate) to provide2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanoneas a brown semi-solid.

Step 4:

A solution of (S)-(−)-2-Butyl-CBS-oxazaborolidine solution (3.0 ml 1.0 Min toluene) and catecholborane (30 ml 1.0 M in THF) was stirred at RTfor 30 min. The mixture was then cooled to −70° C. and2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanone(1 g, 2.9 mmol) in THF (16 mL) was added dropwise. After addition, thereaction mixture was warmed up to −32° C. and stirred for 12 h. Afterthis time, 3N NaOH (18 mL) was added followed by H₂O₂ (18 mL) and thetemperature of the reaction mixture was increased to RT for 30 min andthen extracted with ethyl. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo andpurified by normal phase silica gel column (EtOAc/hepate) to provide thetitle compound as a yellow solid.

Intermediate 38:(R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol

Step 1:

A solution of 2,4-dibromo-benzoic acid, (2.3 g, 18.8 mmol), phenylboronic acid (5 g, 17.9 mmol), Pd₂(dba)₃ (818 mg, 8.9 mmol) and LiOH(1.65 g, 39.3 mmol) in a 1:1 mixture of NMP/water (100 mL) was heated to70° C. for 2 d. After this time, the reaction mixture was cooled to RT,and the reaction mixture was adjusted to pH=4-5 with 3 N HCl. Themixture was then extracted with ethyl acetate and the combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo and purified by normal phase silica gel column(EtOAc/PE 10:1 to 1:1) to afford 5-bromo-[1,1′-biphenyl]-2-carboxylicacid as a colorless oil.

Step 2:

To a solution of 5-bromo-[1,1′-biphenyl]-2-carboxylic acid (5 g, 18.2mmol) in MeOH (30 mL) was added SOCl₂ (10 mL) dropwise. The reactionmixture was heated to 70° C. for 2 h, then cooled to RT. The mixture wasconcentrated, adjusted to pH=7-8 with saturated aqueous NaHCO₃ andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo andpurified by normal phase silica gel column (EtOAc/PE 50:1) to affordmethyl 5-bromo-[1,1′-biphenyl]-2-carboxylate as a colorless oil.

Step 3:

A solution of methyl 5-bromo-[1,1′-biphenyl]-2-carboxylate (2.2 g, 6.9mmol) in THF (50 mL) was cooled to 0° C. LiAlH₄ (380 mg, 10 mmol) wasadded slowly. The reaction mixture was stirred at RT for 2 h, afterwhich water (1 mL) was added slowly to quench the reaction. The solidwas removed by filtration and the filtrate was concentrated in vacuo toprovide (5-bromo-[1,1′-biphenyl]-2-yl)methanol as a white solid that wasused directly without further purification.

Step 4:

To a solution of (5-bromo-[1,1′-biphenyl]-2-yl)methanol (2.0 g, 8.4mmol) in CH₂Cl₂ (30 mL) was added Dess-Martin Periodinane (4.3 g, 10mmol). The reaction mixture was stirred at RT for 2 h and then thesolids were filtered and the resultant filtrate was concentrated invacuo. Purification by normal phase silica gel column (EtOAc:PE=1:50)afforded 5-bromo-[1,1′-biphenyl]-2-carbaldehyde as a colorless oil.

Step 5:

To a solution of 5-bromo-[1,1′-biphenyl]-2-carbaldehyde (1.9 g, 7.3mmol) and was added TMSCF₃ (1.2 g, 8.7 mmol) in THF (20 mL) and cooledto 0° C. To this solution was added TBAF (1.46 mL, 1M in THF) and thereaction mixture was warmed to RT for 3 h. After this time, the mixturewas treated with 3 N HCl (5 mL) and stirred for 12 h. Then the reactionmixture was diluted with water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated in vacuo and purified by normal phase silica gelcolumn (EtOAc:PE=1:10) to afford1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol as a colorlessoil.

Step 6:

To a solution of 1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethano(1.8 g, 5.5 mmol) in CH₂Cl₂ (30 mL) was added Dess-Martin Periodinane (3g, 7.1 mmol). The reaction mixture was stifled at RT for 2 h and thenthe solids were filtered. The resultant filtrate was concentrated invacuo. Purification by normal phase silica gel column (EtOAc:PE=1:50)afforded 1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone as acolorless oil.

Step 7:

1-(5-Bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone (1.3 g, 3.9mmol) in CH₃CN (10 mL) was reduced to the chiral alcohol using thechiral iridium catalyst (METHOD A) at RT. The reaction mixture was thencharged with potassium formate (725 mg, 8.6 mmol) and the mixture wasstirred at 40° C. for 12 h. Then the reaction was diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, concentrated in vacuo andpurified by normal phase silica gel column (EtOAc:PE=1:10) to afford thetitle compound as a colorless oil.

Using the procedure described for Intermediate 3,(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol,the following alcohols (Intermediates 39-42) shown in the Table belowwere prepared starting with the appropriately substituted pyrazole.

LCMS No. Name Structure (MH+) Intermediate 39 (R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethanol

345 Intermediate 40 (R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2- trifluoroethanol

334 Intermediate 41 (R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethanol

319 Intermediate 42 (R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethanol

317

Intermediate 43: (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol

A solution of dichloro(pentamethylcyclopentadienyl)iridium (III) dimer([Cp*IrCl₂]₂, 14 mg, 0.02 mmol) and(1R,2R)-(−)-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (14 mg, 0.04mmol) in water (7 mL) was prepared at RT. The resulting mixture washeated to 40° C. for 3 h to provide a homogeneous orange solution. Tothis active catalyst solution at 40° C. was added potassium formate (143mg, 171 mmol), and a solution of1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanone (CAS#1033805-23-0, 98mg, 0.34 mmol) in CH₃CN (70 mL). The reaction mixture was then stirredat 40° C. for 2 h and then cooled to RT and the layers were separated.The aqueous layer was extracted with MTBE and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo toprovide the title compound that was used without further purification.

The following alcohols and amines in the table below are useful inpreparing compounds of the invention. They are either commerciallyavailable or can be prepared by known synthetic procedures. CAS registrynumbers are provided for each.

No. Name CAS Registry # Structure Ex # 21(R)-2,2,2-trifluoro-1-(2-(3-methyl-1H- pyrazol-1-yl)phenyl)ethanol1033805-15-0

10a & 10e 22 (R)-1-(2-bromo-4-chlorophenyl)-2,2,2- trifluoroethanol1033805-25-2

34a-34ae 23 (R)-1-(5-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol 1033805-72-9

10k 24 1-(adamantan-1-yl)ethanamine 13392-28-4

38 25 (adamantan-1-yl)methanamine 17768-41-1

41c 26 [1,1′-biphenyl]-3-ylmethanamine 177976-49-7

39d 27 naphthalen-2-ylmethanamine 2018-90-8

39a 28 1-(adamantan-1-yl)ethanol 26750-08-3

41c 29 (R)-1-(naphthalen-2-yl)ethanamine 3906-16-9

39e 30 (R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethanol 68200-42-0

59b 31 [1,1′-biphenyl]-4-ylmethanamine 712-76-5

39b 32 (2-(piperidin-1-yl)phenyl)methanamine 72752-54-6

41a 33 (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol 80418-12-8

55a-55db No. = Intermediate number; Ex # = Used in the preparation ofthe following example(s)Preparation of Boronic Acids and Esters

The boronic acids and esters used in biaryl couplings are eithercommercially available or can be readily synthesized from thecorresponding bromide using routine synthetic methods. The followingIntermediate 34 is a representative example.

Intermediate 34:6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one

To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (200 mg, 0.89mmol) in 5 mL of acetonitrile was added pinacoldiboron (300 mg, 1.2mmol), Pd(dppf)₂Cl (30 mg, 0.09 mmol), KOAc (250 mg, 2.1 mmol) andtriethyl amine (1 mL). The reaction was heated to 87° C. for 24 h, thencooled to RT. The solids were filtered away, and the solvent was removedin vacuo, then extracted with EtOAc, water, brine and dried over Na₂SO₄.The solvent was removed in vacuo to provide an off-white solid which wasused without further purification.

Spirocyclic Amino Esters Preparation Intermediate 35: (S)-2-Benzyl3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

Step 1:

(3S)-8-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate[Example 24 in US Pat. Pub. No. 2012/0101280] (50 g, 160 mmol) in CH₂Cl₂(500 mL), and Et₃N (51.7 g, 512 mmol) was cooled to 0° C. Benzylchloroformate (34.1 g, 205 mmol) was added dropwise and the mixture wasstirred at 0° C. for 3 h. The reaction mixture was washed with water,extracted with CH₂Cl₂, dried over Na₂SO₄, and concentrated in vacuo toprovide (S)-2-benzyl 8-tert-butyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate as a light yellow oilwhich was used directly without further purification.

Step 2:

To a solution of (S)-2-benzyl 8-tert-butyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3,8-tricarboxylate (79 g, 160 mmol, Step 1)in CH₂Cl₂ (400 mL) was added TFA (182 g, 1600 mmol) dropwise at RT. Thereaction mixture was stirred for 3 h then concentrated in vacuo. Theresidue was quenched with saturated NaHCO₃ and solid NaHCO₃ was addeduntil no further gas evolution was noted. The mixture was extracted withEtOAc and the combined organic layers were concentrated in vacuo.Purification by normal phase silica gel column chromatography(CH₂Cl₂/MeOH/NH₄OH) provided the title compound as a light yellow solid.

Intermediate 36: (S)-2-Tert-butyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate

Step 1:

(S)-2-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.4 g,6.9 mmol) in HCl/dioxane (50 mL, 3.3 N) was stirred for 2 h at RT. Thesolvent was then removed in vacuo to provide (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride which was useddirectly without further purification.

Step 2:

To a solution of (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride and BOC₂O (1.5g, 6.9 mmol) in EtOH (50 mL) was added Pd/C (10%, 2.4 g) and HOAc(cat.). The mixture was degassed and blanked under H₂ then stirred at45° C. at 50 psi of H₂ for 12 h. The solid was filtered away and thefiltrate concentrated in vacuo to provide the title compound as aviscous solid.

Intermediate 37: Methyl 3,9-diazaspiro[5.5]undecane-2-carboxylate

To a solution of 3,9-diazaspiro[5.5]undecane-2-carboxylic acid,3-[(4-methoxyphenyl)methyl]-9-(phenylmethyl)-methyl ester[CAS#1314388-32-3] (50 mg, 0.12 mmol) in MeOH (2 mL) and water (2 mL)was added a catalytic amount of TFA. The mixture was hydrogenated usinga H-cube apparatus under 80° C./80 bar 2 cycles. The reaction mixturewas cooled to RT then concentrated in vacuo to provide the titlecompound as a white solid which is used directly.

General Synthetic Methods

Methods for Removal of N-Carbobenzyloxy (N-CBZ) Protecting Group

Method A—Hydrogenation Over Pd/C:

To a solution of N-CBZ protected compound (1 eq.) in EtOAc was addedHOAc (100 μL) and 5% (w/w) Pd/C (5 mol %). The reaction mixture wasdegassed, blanketed under H₂ (balloon) 3 times, then stirred at RT for 2h. The reaction was then filtered through a pad of celite that wasrinsed with 1:9 MeOH:EtOAc. The filtrate was concentrated in vacuo. Theproduct was purified by column chromatography using an Isco Goldreversed phase silica cartridge (H₂O:HOAc: 99:1 to MeOH:AcOH 99:1).

Method B—Dealkylation with TMSI:

To a solution of N-CBZ protected compound (1 eq.) in CH₃CN was added asolution of TMSI (2.2 eq.) in CH₃CN (0.2 M). The reaction mixture wasstirred at RT for 2 h then quenched with 1 N HCl to pH 1. The productwas purified by column chromatography using an Isco Gold reversed phasesilica cartridge (H₂O:HOAc: 99:1 to MeOH:AcOH 99:1).

General Ester Hydrolysis with Lithium Hydroxide:

To a solution of an ethyl ester compound (1 eq) in THF (0.18 M) andwater (1.4 M) was added LiOH—H₂O (10 eq). The mixture was stirred at RTfor 1 h. Water was added and the pH was adjusted to 6.5 with 1 N HCl.THF was removed in vacuo, then the solid was precipitated, washed withwater, and dried in vacuo to yield the corresponding carboxylic acid.

The compounds of the examples were isolated either in the neutralzwitterionic form or as a TFA or HCl salt.

Example 1u:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(160 mg, 0.2 mmol, Intermediate 1) in dioxane (2 mL) was added2-amino-4,6-dichloropyrimidine (100 mg, 0.16 mmol) and Cs₂CO₃ (48 g,0.16 mmol). The reaction was heated to 80° C. for 16 h, cooled to RT,and filtered. The solvent was removed in vacuo and the residue wasdissolved in a mixture of CH₂Cl₂ and heptane, concentrated to half thevolume, filtered, and concentrated again in vacuo. Purification vianormal phase silica gel chromatography (CH₂Cl₂/Heptane) provided4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloro-pyrimidin-2-amineas an off-white solid.

Step 2:

To a solution of4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloro-pyrimidin-2-amine(125 mg, 0.3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol)and Na₂CO₃ (182 mg, 0.35 mmol). The reaction was heated to 90° C. for130 h, then cooled to RT, filtered, and concentrated in vacuo.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) wasadded phenylboronic acid (143 mg, 0.8 mmol), PdCl₂(PPh₃)₂ (41 mg, 0.058mmol), and Cs₂CO₃ (390 mg, 1.2 mmol). The reaction was heated to 60° C.for 16 h, then cooled to RT, filtered through celite and concentrated invacuo. Purification by normal phase silica gel column (EtOAc/heptane)provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 4:

A solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(240 mg, 0.4 mmol, Step 3) in EtOAc (5 mL) was hydrogenated using anH-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane)provided (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 5:

To a solution of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(50 mg, 0.08 mmol) from Step 4 in THF (2.0 mL) and water (0.2 mL), wasadded lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reactionmixture was stirred at RT for 2 h, then the solution was neutralizedwith 1 N HCl, and concentrated in vacuo. Purification by normal phasesilica gel column (EtOAc/heptane) provided the title compound as anoff-white solid as the zwitterionic form.

Example 1m:(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) andwater (0.5 mL) was added (3,4-dimethylphenyl)boronic acid (120 mg, 0.8mmol), PdCl₂(PPh₃)₂ (41 mg, 0.058 mmol), and Cs₂CO₃ (390 mg, 1.2 mmol).The reaction was heated to 60° C. for 16 h, then cooled to RT, filteredthrough celite and concentrated in vacuo. Purification by normal phasesilica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

A solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(220 mg, 0.3 mmol) in EtOAc (5 mL) was hydrogenated using an H-Cubeapparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/minat RT. Purification on normal phase silica gel (EtOAc/heptane) provided(S)-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 3:

To a solution of (S)-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), wasadded lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reactionmixture was stirred at RT for 2 h, then the solution was neutralizedwith 1 N HCl and concentrated in vacuo. Purification by normal phasesilica gel column (EtOAc/heptane) provided the title compound as anoff-white solid as the zwitterionic form.

Example 1cg:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) andwater (0.5 mL) was added (3-(hydroxymethyl)-4-methylphenyl)boronic acid(CAS#1451391-54-0; 120 mg, 0.7 mmol), PdCl₂(PPh₃)₂ (41 mg, 0.058 mmol),and Cs₂CO₃ (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16h, then cooled to RT, filtered through celite and concentrated in vacuo.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylatea white solid.

Step 2:

A solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(200 mg, 0.24 mmol,) in EtOAc (5 mL) was hydrogenated using an H-Cubeapparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/minat RT. Purification on normal phase silica gel (EtOAc/heptane) provided(S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 3:

To a solution of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), wasadded lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reactionmixture was stirred at RT for 2 h, then the solution was neutralizedwith 1 N HCl, and concentrated in vacuo. Purification by normal phasesilica gel column (EtOAc/heptane) provided the title compound as anoff-white solid as the zwitterionic form.

Example 1cr:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(hydroxymethyl)-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made as described for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 1cq) using (4-(hydroxymethyl)-3-methylphenyl)boronic acid(CAS#1218790-88-5).

Using the generic scheme below, the following examples of Table 1a wereprepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 1u). The boronic acid was generally used to make theanalogues below, however, where it was not available, the correspondingboronate was used.

TABLE 1a

Ex. LCMS No. Cy CAS Name (MH+) 1a

(3S)-8-(2-amino-6-((1R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(methylsulfinyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 671 1b

(S)-8-(2-amino-6-((R)-2,2,2-trifuoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(methylthio)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 655 1c

(S)-8-(2-amino-6-((R)-1-(3′-carboxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652 1d

(S)-8-(2-amino-6-((R)-1-(3′-carboxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652.5 1e

(S)-8-(2-amino-6-((R)-1-(4′-carboxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652.6 1f

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 613.5 1g

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 609.6 1h

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 612.6 1i

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoxazol-4-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 599.6 1j

(S)-8-(2-amino-6-((R)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 614.6 1k

(S)-8-(6-((R)-1-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 655.7 1l

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 666.7 1m

(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 636.7 1n

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 639.6 1o

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-indazol-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 662.3 1p

(S)-8-(2-amino-6-((R)-1-(4′-(tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 664.8 1q

(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652.7 1r

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyrimidin-5-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 639.6 1s

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 639.6 1u

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid608.6 1v

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 636 1w

(S)-8-(2-amino-6-((R)-1-(3′-cyano-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 633 1x

(S)-8-(6-((R)-1-(4′-(acetamidomethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 679 1y

(S)-8-(6-((R)-1-(4′-(2-acetamidoethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 693 1z

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 659 1aa

(S)-8-(6-((R)-1-(4-(1H-indo1-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid 5671ab

(S)-8-(2-amino-6-((R)-1-(4′-(aminomethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 637 1ac

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 626 1ad

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 659 1ae

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 622 1af

(S)-8-(2-amino-6-((R)-1-(3′,4′-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 677 1ag

(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 644 1ah

(S)-8-(2-amino-6-((R)-1-(4′-chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 643 1ai

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyrimidin-5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 610 1ak

(S)-8-(2-amino-6-((R)-1-(3′-chloro-3-(3-methyl-1H-pyrazol-1-yl)-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 711 1al

(S)-8-(2-amino-6-((R)-1-(3′-chloro-4′-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 687 1am

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 676 1an

(S)-8-(2-amino-6-((R)-1-(3′-chloro-5′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 1ao

(S)-8-(2-amino-6-((R)-1-(4′-chloro-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 661 1ap

(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652 1aq

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 640 1ar

(S)-8-(2-amino-6-((R)-1-(3′-chloro-4′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 661 1as

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 692 1at

(S)-8-(2-amino-6-((R)-1-(3′,5′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 637 1au

(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 644 1av

(S)-8-(2-amino-6-((R)-1-(3′,5′-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 644 1aw

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-3(trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 694 1ax

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 684 1ay

(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-5′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 670 1az

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 664 1ba

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-fluoro-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 640 1bb

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-isopropyl-3-(3-methyl-1H-pyrazol-1-yl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 650 1bc

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 666 1bd

(S)-8-(2-amino-6-((R)-1-(4′-chloro-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 656 1be

(S)-8-(2-amino-6-((R)-1-(3′-carbamoyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 651 1bf

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3′,5′- bis(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid744 1bg

(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-4′-fluoro-3-(3-methyl-1H-pyrazol-1-yl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 670 1bh

(S)-8-(2-amino-6-((R)-1-(4′-chloro-3′,5′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 671 1bi

(S)-8-(2-amino-6-((R)-1-(3′,5′-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 677 1bj

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 778 1bk

(S)-8-(2-amino-6-((R)-1-(3′-chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 642 1bl

(S)-8-(2-amino-6-((R)-1-(3′-chloro-3-(3-methyl-1H-pyrazol-1-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 711 1bm

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 638 1bn

(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 670 1bo

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′,4′,5′-trifluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 662 1bp

(S)-8-(2-amino-6-((R)-1-(3′-chloro-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 657 1bq

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-4′-(trifluoromethoxy)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 706 1br

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-5′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 684 1bs

(S)-8-(2-amino-6-((R)-1-(3′-chloro-5′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 661 1bt

(S)-8-(2-amino-6-((R)-1-(4′-chloro-3-(3-methyl-1H-pyrazol-1-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 710 1bu

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-5′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 694 1bv

(S)-8-(2-amino-6-((R)-1-(3′-chloro-4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 701 1bw

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(naphthalen-2-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 659 1bx

(S)-8-(2-amino-6-((R)-1-(4′-(benzyloxy)-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 733 1by

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 681 1bz

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 685 1ca

(S)-8-(2-amino-6-((R)-1-(4′-butoxy-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 698 1cb

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid709 1cc

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 687 1cd

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 668 1ce

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-((2-morpholinoethypcarbamoyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid764 1cf

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-sulfamoyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 689 1cg

(S)-8-(2-amino-6-((R)-1-(4′-carbamoyl-3-(3-methyl-1H-pyrazol-1-yl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652 1ch

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(methylcarbamoyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 666 1ci

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 657 1cj

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(piperazine-1- carbonyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid721 1ck

(S)-8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 680 1cl

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isobutoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 681 1cm

(S)-8-(2-amino-6-((R)-1-(4′-(diethylcarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 707 1cn

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(neopentyloxy)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 695 1co

(S)-8-(2-amino-6-((R)-1-(4-(chroman-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 665 1cp

(S)-8-(2-amino-6-((R)-1-(4-(cinnolin-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 661 1cq

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652 1cr

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(hydroxymethyl)-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 653 1cs

(S)-8-(2-amino-6-((R)-1-(4-(6-ethoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 654 1ct

(S)-8-(2-amino-6-((S)-1-(3′,4′-bis(hydroxymethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 669

TABLE 1b 1H NMR Data for Compounds of Table 1a Ex. No. 1H NMR 1a ¹H NMR(MeOH-d4): δ ppm 1.29 (m, 3H), 1.68 (q, J = 6.3 Hz, 4H), 2.10 (dd, J =13.6, 8.1 Hz, 1H), 2.41 (s, 4H), 2.85 (s, 3H), 3.24 (m, 2H), 3.62 (m,1H), 3.71 (s, 2H), 3.79 (dd, J = 13.7, 5.8 Hz, 2H), 4.44 (t, J = 8.5 Hz,1H), 4.83 (s, 2H), 6.44 (d, J = 2.4 Hz, 1H), 6.92 (q, J = 6.2 Hz, 1H),7.88 (m, 8H) 1b ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 3H), 1.60 (t,J = 5.6 Hz, 4H), 2.06 (dd, J = 13.4, 7.0 Hz, 1H), 2.40 (s, 4H), 2.51 (s,3H), 2.80 (s, 1H), 3.13 (d, J = 11.5 Hz, 1H), 3.25 (d, J = 11.0 Hz, 1H),3.53 (dd, J = 22.1, 9.7 Hz, 2H), 3.69 (d, J = 14.9 Hz, 2H), 4.14 (t, J =8.1 Hz, 1H), 4.93 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.79 (q, J = 6.5Hz, 1H), 7.34 (m, 2H), 7.63 (dd, J = 8.9, 2.1 Hz, 3H), 7.77 (m, 2H),7.97 (d, J = 2.3 Hz, 1H) 1c ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.4 (d, J =18.0 Hz, 1H), 1.68 (q, J = 6.8, 5.6 Hz, 4H), 2.4 (dd, J = 13.6, 8.1 Hz,1H), 2.41 (s, 4H), 2.85 (s, 1H), 3.25 (m, 2H), 3.64 (m, 1H), 3.72 (s,1H), 3.79 (d, J = 13.8 Hz, 2H), 4.44 (q, J = 8.6 Hz, 1H), 6.5 (d, J =2.4 Hz, 1H), 6.92 (dd, J = 10.5, 4.4 Hz, 1H), 7.95 (m, 5H), 8.1 (d, J =2.5 Hz, 1H), 8.4 (m, 2H) 1d ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.68 (dt, J= 9.0, 5.8 Hz, 4H), 2.09 (dd, J = 13.6, 8.1 Hz, 1H), 2.41 (s, 4H), 3.24(m, 2H), 3.72 (m, 4H), 4.45 (t, J = 8.5 Hz, 1H), 6.44 (d, J = 2.3 Hz,1H), 6.90 (q, J = 6.2 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.75 (d, J =1.7 Hz, 1H), 7.85 (m, 2H), 7.98 (m, 2H), 8.08 (dt, J = 7.8, 1.3 Hz, 1H),8.34 (t, J = 1.8 Hz, 1H) 1e ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.68 (dt, J= 9.0, 5.8 Hz, 4H), 2.09 (dd, J = 13.6, 8.1 Hz, 1H), 2.41 (s, 4H), 3.24(m, 2H), 3.72 (m, 4H), 4.45 (t, J = 8.5 Hz, 1H), 6.44 (d, J = 2.3 Hz,1H), 6.90 (q, J = 6.2 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.75 (d, J =1.7 Hz, 1H), 7.85 (m, 2H), 7.98 (m, 2H), 8.08 (dt, J = 7.8, 1.3 Hz, 1H),8.34 (t, J = 1.8 Hz, 1H) 1f ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.47-1.69(m, 4 H) 1.97-2.13 (m, 1 H) 2.19-2.35 (m, 1 H) 2.37 (d, J = 0.34 Hz, 0H) 2.66-2.81 (m, 2 H) 3.05-3.17 (m, 1 H) 3.18-3.28 (m, 1 H) 3.33-3.40(m, 2 H) 3.41-3.72 (m, 4 H) 3.73-3.83 (m, 2 H) 3.99-4.13 (m, 1 H) 5.71(s, 1 H) 6.32 (d, J = 0.39 Hz, 1 H) 6.41 (d, J = 2.29 Hz, 2 H) 6.67-6.79(m, 1 H) 7.49 (d, J = 1.81 Hz, 1 H) 7.55-7.64 (m, 1 H) 7.72 (d, J = 8.40Hz, 2 H) 7.92 (d, J = 2.29 Hz, 1 H) 1g ¹H NMR (400 MHz, MeOH-d4): δ ppm1.49-1.69 (m, 4 H) 2.06 (dd, J = 13.47, 7.03 Hz, 1 H) 2.31 (dd, J =13.42, 9.32 Hz, 1 H) 2.41 (s, 3 H) 3.12 (d, J = 12.00 Hz, 1 H) 3.25 (d,J = 11.76 Hz, 1 H) 3.38-3.57 (m, 2 H) 3.58-3.76 (m, 2 H) 4.08 (dd, J =9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.44 (d, J = 2.34 Hz, 1 H) 6.87 (q, J= 6.62 Hz, 1 H) 7.75-7.80 (m, 2 H) 7.82 (s, 1 H) 7.89 (s, 2 H) 8.02 (d,J = 2.34 Hz, 1 H), 8.57-8.69 (m, 2 H) 1h ¹H NMR (400 MHz, MeOH-d4): δppm 1.61-1.84 (m, 5 H) 2.10 (dd, J = 13.62, 8.49 Hz, 1 H) 2.40 (s, 3 H)2.47 (dd, J = 13.76, 8.88 Hz, 1 H) 3.25-3.29 (m, 2 H) 3.73-3.91 (m, 4 H)3.94 (s, 3 H) 4.53 (t, J = 8.64 Hz, 1 H) 6.42 (d, J = 2.39 Hz, 1 H) 6.81(q, J = 5.94 Hz, 1 H) 7.61-7.70 (m, 2 H) 7.71-7.78 (m, 1 H) 7.90-7.96(m, 2 H) 8.12 (s, 1 H) 1i ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35-1.40 (m,5 H), 1.60-1.65 (m, 8 H), 2.40 (m, 5 H) 2.47 (dd, J = 13.76, 8.88 Hz, 1H) 3.25-3.29 (m, 2 H) 3.73-3.91 (m, 4 H) 3.94 (s, 3 H) 4.53 (t, J = 8.64Hz, 1 H), 5.6 (s, 1H), 6.42 (d, J = 2.39 Hz, 2 H) 6.70 (m, 1 H)7.61-7.70 (m, 2 H) 7.71-7.78 (m, 1 H) 7.90-7.96 (m, 2 H) 8.12 (s, 1 H)1j ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58-1.86 (m, 4 H) 2.01-2.20 (m, 1H) 2.40 (s, 3 H) 2.43-2.61 (m, 3 H) 3.61-3.75 (m, 2 H) 3.86 (s, 4 H)3.93 (t, J = 5.44 Hz, 2 H) 4.25-4.37 (m, 2 H) 4.49-4.69 (m, 1 H) 6.42(d, J = 2.24 Hz, 2 H) 6.52 (br. s., 1 H) 6.77-6.88 (m, 1 H) 7.51 (d, J =1.32 Hz, 1 H) 7.60-7.73 (m, 2 H) 7.91 (d, J = 2.34 Hz, 1 H) 1k ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.72 (d, J = 18.21 Hz, 4 H) 2.09 (dd, J =13.62, 8.49 Hz, 1 H) 2.18 (d, J = 14.50 Hz, 3 H) 2.39 (s, 3 H) 2.48 (dd,J = 13.64, 8.91 Hz, 1 H) 2.58 (br. s., 1 H) 2.66 (br. s., 1 H) 3.60-3.95(m, 6 H) 4.24 (br. s., 2 H) 4.55 (t, J = 8.71 Hz, 1 H) 6.33 (br. s., 1H) 6.42 (d, J = 2.34 Hz, 1 H) 6.46 (br. s., 1 H) 6.75-6.87 (m, 1 H) 7.52(s, 1 H) 7.62-7.74 (m, 2 H) 7.92 (d, J = 2.34 Hz, 1 H) 1l ¹H NMR (400MHz, MeOH-d4): δ ppm 1.29 (d, J = 6.05 Hz, 6 H) 1.49 (d, J = 5.47 Hz, 4H) 1.70-1.86 (m, 1 H) 1.98-2.15 (m, 1 H) 2.37 (s, 3 H) 2.69 (d, J =11.13 Hz, 1 H) 2.93 (s, 1 H) 3.35-3.52 (m, 2H) 3.53-3.64 (m, 2 H)3.64-3.73 (m, 1 H) 4.59 (s, 1 H) 5.71 (s, 1 H) 6.38 (d, J = 2.15 Hz, 1H) 6.68-6.82 (m, 1 H) 6.93 (d, J = 8.79 Hz, 2 H) 7.44-7.58 (m, 3 H) 7.64(d, J = 1.37 Hz, 1 H) 7.67-7.78 (m, 1 H) 7.93 (d, J = 2.15 Hz, 1 H) 1m¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51 (d, J = 5.47 Hz, 4 H) 1.71-1.86(m, 1 H) 2.01-2.17 (m, 1 H) 2.28 (s, 3 H) 2.31 (s, 3 H) 2.39 (s, 3 H)2.64-2.78 (m, 1 H) 2.90-3.05 (m, 1 H) 3.36-3.54 (m, 2 H) 3.55-3.79 (m, 3H) 5.73 (s, 1 H) 6.41 (d, J = 2.15 Hz, 1 H) 6.69-6.87 (m, 1 H) 7.20 (s,1 H) 7.33-7.40 (m, 1 H) 7.43 (s, 1 H) 7.59 (d, J = 1.37 Hz, 1 H) 7.70(s, 1 H) 7.75 (s, 1 H) 7.96 (d, J = 2.15 Hz, 1 H) 1n ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.53 (d, J = 5.86 Hz, 4 H) 1.75-1.87 (m, 1 H) 2.04-2.17(m, 1 H) 2.41 (s, 3 H) 2.64-2.76 (m, 1 H) 2.91-3.04 (m, 1 H) 3.38-3.54(m, 2 H) 3.55-3.74 (m, 3 H), 3.95 (s, 3 H) 5.72 (s, 1 H) 6.44 (d, J =2.34 Hz, 1 H) 6.79-6.92 (m, 1 H) 7.12 (s, 1 H) 7.23-7.31 (m, 1 H) 7.74(d, J = 1.17 Hz, 1 H) 7.79-7.89 (m, 2 H) 8.02 (d, J = 2.15 Hz, 1 H)8.15-8.25 (m, 1 H) 1o ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (br. s., 4H) 2.02-2.17 (m, 1 H) 2.24-2.39 (m, 1 H) 2.43 (s, 3 H) 2.53-2.66 (m, 4H) 3.07-3.17 (m, 1 H) 3.21-3.29 (m, 1 H) 3.40-3.59 (m, 2 H) 3.61-3.80(m, 2 H) 4.00-4.18 (m, 1 H) 5.77 (s, 1 H) 6.45 (d, J = 2.15 Hz, 1 H)6.75-6.90 (m, 1 H) 7.36-7.56 (m, 1 H) 7.73 (d, J = 4.10 Hz, 2 H)7.77-7.89 (m, 4 H) 8.01 (d, J = 2.15 Hz, 1 H) 1p ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.24-1.42 (m, 9 H) 1.60 (br. s., 4 H) 2.02-2.12 (m, 1 H)2.42 (s, 4 H) 3.05-3.17 (m, 1 H) 3.20-3.29 (m, 1 H) 3.41-3.79 (m, 4 H)4.02-4.17 (m, 1 H) 5.78 (s, 1 H) 6.43 (d, J = 2.15 Hz, 1 H) 6.73-6.88(m, 1 H) 7.51 (d, J = 8.40 Hz, 2 H) 7.57-7.69 (m, 3 H) 7.78 (s, 2 H)7.98 (d, J = 2.15 Hz, 1 H) 1q ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t,J = 7.03 Hz, 3 H) 1.60 (br. s., 4 H) 1.95-2.14 (m, 1 H) 2.27-2.38 (m, 1H) 2.41 (s, 3 H) 3.14 (s, 1 H) 3.20-3.29 (m, 1 H) 3.41-3.59 (m, 2 H)3.60-3.83 (m, 2 H) 3.99-4.20 (m, 3 H) 5.77 (s, 1 H) 6.43 (d, J = 2.34Hz, 1 H) 6.71-6.85 (m, 1H) 7.00 (d, J = 8.79 Hz, 2 H) 7.52-7.65 (m, 3 H)7.72 (d, J = 1.56 Hz, 1 H) 7.76 (s, 1 H) 7.97 (d, J = 2.34 Hz, 1 H) 1r¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (d, J = 4.88 Hz, 4 H) 2.02-2.13(m, 1 H) 2.27-2.38 (m, 1 H) 2.42 (s, 3 H) 3.16 (s, 1 H) 3.26 (s, 1H)3.41-3.59 (m, 2 H) 3.60-3.78 (m, 2 H) 3.99-4.19 (m, 4 H) 5.76 (s, 1 H)6.45 (d, J = 2.34 Hz, 1 H) 6.82-6.96 (m, 1 H) 7.74 (d, J = 1.56 Hz, 1 H)7.81 (d, J = 1.56 Hz, 1 H) 7.86 (s, 1 H) 8.03 (d, J = 2.15 Hz, 1 H) 8.92(s, 2 H)) 1s ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (br. s., 4 H)2.01-2.14 (m, 1 H) 2.31 (br. s., 1 H) 2.41 (s, 3 H) 3.07-3.17 (m, 1 H)3.21-3.29 (m, 1 H) 3.40-3.59 (m, 2 H) 3.67 (d, J = 5.47 Hz, 2 H) 3.95(s, 3 H) 4.09 (d, J = 1.17 Hz, 1 H) 5.75 (s, 1 H) 6.43 (d, J = 2.15 Hz,1 H) 6.82 (d, J = 6.44 Hz, 1 H) 6.88 (d, J = 8.79 Hz, 1 H) 7.64 (d, J =1.56 Hz, 1 H) 7.68-7.76 (m, 1 H) 7.77-7.87 (m, 1 H) 7.93-8.07 (m, 2 H)8.45 (d, J = 2.34 Hz, 1 H) 1u ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.42-1.74(m, 4 H) 2.05 (dd, J = 13.50, 7.20 Hz, 1 H) 2.40 (s, 4 H) 3.07-3.16 (m,1 H) 3.17-3.29 (m, 1 H) 3.38-3.59 (m, 2 H) 3.59-3.78 (m, 2 H) 4.11 (dd,J = 9.10, 7.25 Hz, 1 H) 6.42 (d, J = 2.34 Hz, 1 H) 6.74-6.86 (m, 1 H)7.34-7.41 (m, 1 H) 7.42-7.50 (m, 2 H) 7.60-7.69 (m, 3 H) 7.71-7.77 (m, 1H) 7.77-7.83 (m, 1 H) 7.97 (d, J = 2.00 Hz, 1 H) 1v ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.24 (t, J = 7.59 Hz, 3 H) 1.50-1.69 (m, 4 H) 2.06 (dd,J = 13.42, 7.13 Hz, 1 H) 2.32 (dd, J = 13.45, 9.20 Hz, 1 H) 2.37 (s, 3H) 2.72 (q, J = 7.61 Hz, 2 H) 3.08-3.27 (m, 2 H) 3.39-3.78 (m, 4 H) 4.08(dd, J = 9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36 (d, J = 2.34 Hz, 1 H)6.71 (q, J = 6.65 Hz, 1 H) 7.26-7.34 (m, 1 H) 7.35-7.44 (m, 1 H) 7.56(s, 1 H) 7.82 (d, J = 2.29 Hz, 1 H) 1w ¹H NMR (400 MHz, MeOH-d4): δ ppm1.51-1.64 (m, 4 H) 1.96 (s, 2 H) 2.04 (dd, J = 13.23, 7.32 Hz, 1 H)2.25-2.34 (m, 1 H) 2.38 (s, 3 H) 3.09 (d, J = 11.67 Hz, 1 H) 3.23 (d, J= 11.81 Hz, 1 H) 3.38-3.56 (m, 2 H) 3.59-3.73 (m, 2 H) 4.00-4.10 (m, 1H) 5.73 (s, 1 H) 6.41 (d, J = 2.34 Hz, 1 H) 6.79-6.89 (m, 1 H) 7.61-7.67(m, 1 H) 7.69-7.88 (m, 4 H) 7.96-8.02 (m, 2 H) 8.08 (t, J = 1.59 Hz, 1H) 1x ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.49-1.64 (m, 4 H) 1.97 (s, 3 H)1.98 (s, 3 H) 2.04 (dd, J = 13.35, 7.15 Hz, 1 H) 2.29 (dd, J = 13.47,9.18 Hz, 1 H) 2.38 (s, 3 H) 3.05-3.26 (m, 2 H) 3.39-3.73 (m, 4 H) 4.05(dd, J = 9.18, 7.22 Hz, 1 H) 4.38 (s, 2 H) 5.73 (s, 1 H) 6.40 (d, J =2.29 Hz, 1 H) 6.77 (q, J = 6.67 Hz, 1 H) 7.37 (d, J = 8.40 Hz, 2 H)7.59-7.66 (m, 3 H) 7.71-7.81 (m, 2 H) 7.95 (d, J = 2.34 Hz, 1 H) 1y ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 4.44 Hz, 4 H) 1.89 (s, 3 H)1.97 (s, 4 H) 2.04 (dd, J = 13.37, 7.13 Hz, 1 H) 2.29 (dd, J = 13.28,9.18 Hz, 1 H) 2.38 (s, 3 H) 2.82 (t, J = 7.32 Hz, 2 H) 3.06-3.25 (m, 2H) 3.40 (t, J = 7.32 Hz, 2 H) 3.43-3.73 (m, 4 H) 4.05 (dd, J = 9.18,7.27 Hz, 1 H) 5.74 (s, 1 H) 6.40 (d, J = 2.25 Hz, 1 H) 6.77 (q, J = 6.80Hz, 1 H) 7.31 (d, J = 8.30 Hz, 2 H) 7.57-7.63 (m, 3H) 7.70-7.80 (m, 2 H)7.95 (d, J = 2.34 Hz, 1 H) 1z ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.53-1.61(m, 4 H) 1.97 (s, 3 H) 2.04 (dd, J = 13.32, 7.03 Hz, 1 H) 2.30 (dd, J =13.59, 9.30 Hz, 1 H) 2.40 (s, 3 H) 3.06-3.26 (m, 2 H) 3.40-3.72 (m, 4 H)4.06 (dd, J = 8.91, 7.25 Hz, 1 H) 5.76 (s, 1 H) 6.42 (d, J = 2.29 Hz, 1H) 6.85 (q, J = 6.51 Hz, 1 H) 7.55 (dd, J = 8.27, 4.32 Hz, 1 H) 7.82 (d,J = 1.71 Hz, 1 H) 7.85-7.99 (m, 3 H) 8.00-8.07 (m, 2 H) 8.29 (s, 1 H)8.39 (d, J = 7.61 Hz, 1 H) 8.88 (dd, J = 4.30, 1.66 Hz, 1 H) 1aa ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.59 (d, J = 4.69 Hz, 4 H) 1.99-2.13 (m, 1 H)2.24-2.39 (m, 1 H) 3.03-3.14 (m, 1 H) 3.17-3.27 (m, 1 H) 3.38-3.54 (m, 2H) 3.55-3.75 (m, 2 H) 3.99-4.14 (m, 1 H) 5.56 (s, 1 H) 6.46 (d, J = 2.93Hz, 1 H) 6.58-6.71 (m, 1 H) 7.27 (d, J = 3.12 Hz, 1 H) 7.29-7.36 (m, 1H) 7.54-7.66 (m, 4 H) 7.70 (d, J = 8.20 Hz, 2 H) 1ab ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.52-1.62 (m, 4 H) 1.92 (s, 5 H) 1.99-2.09 (m, 1 H) 2.27(dd, J = 13.42, 9.22 Hz, 1 H) 2.38 (s, 3 H) 3.06-3.26 (m, 2 H) 3.39-3.73(m, 4 H) 4.00-4.08 (m, 1 H) 4.13 (s, 2 H) 5.72 (s, 1 H) 6.41 (d, J =2.29 Hz, 1 H) 6.78 (q, J = 6.49 Hz, 1 H) 7.53 (d, J = 8.30 Hz, 2 H) 7.66(d, J = 1.66 Hz, 1 H) 7.73-7.84 (m, 4 H) 7.97 (d, J = 2.25 Hz, 1 H) 1ac¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51-1.70 (m, 4 H) 2.06 (dd, J = 13.37,7.13 Hz, 1 H) 2.31 (dd, J = 13.28, 9.37 Hz, 1 H) 2.41 (s, 3 H) 3.08-3.19(m, 1 H) 3.20-3.29 (m, 1 H) 3.39-3.78 (m, 4 H), 4.01-4.19 (m, 1 H) 5.75(s, 1 H) 6.43 (d, J = 2.15 Hz, 1 H) 6.84 (d, J = 6.64 Hz, 1 H) 7.06-7.19(m, 1 H) 7.37-7.52 (m, 3 H) 7.65 (d, J = 1.56 Hz, 1 H) 7.70-7.77 (m, 1H) 7.78-7.86 (m, 1 H) 8.00 (d, J = 2.15 Hz, 1 H) 1ad ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.53-1.68 (m, 4 H) 2.00-2.11 (m, 1 H) 2.25-2.36 (m, 1 H)2.44 (s, 3 H) 3.03-3.13 (m, 1 H) 3.18-3.26 (m, 1 H) 3.42-3.60 (m, 2 H)3.62-3.80 (m, 2 H) 3.98-4.12 (m, 1 H) 5.73-5.86 (m, 1 H) 6.38-6.53 (m, 1H) 6.80-6.96 (m, 1 H) 7.56-7.64 (m, 1 H) 7.82-7.93 (m, 2 H) 7.93-8.00(m, 1 H) 8.03-8.09 (m, 1 H) 8.16 (s, 2 H) 8.28-8.38 (m, 1 H), 8.42-8.55(m, 1 H) 8.80-8.97 (m, 1 H) 1ae ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89(t, J = 6.7 Hz, 1H), 1.30 (d, J = 16.8 Hz, 3H), 1.57 (q, J = 8.1, 5.5Hz, 4H), 1.98 (m, 1H), 2.24 (m, 1H), 2.38 (d, J = 10.5 Hz, 6H), 2.99 (d,J = 11.6 Hz, 1H), 3.16 (d, J = 11.5 Hz, 1H), 3.48 (ddt, J = 20.2, 13.1,6.1 Hz, 3H), 3.65 (dd, J = 13.9, 6.2 Hz, 2H), 3.96 (t, J = 8.0 Hz, 1H),5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.77 (q, J = 6.6 Hz, 1H), 7.26(d, J = 7.8 Hz, 2H), 7.58 (m, 3H), 7.74 (m, 2H), 7.96 (d, J = 2.4 Hz,1H) 1af ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (m, 1H), 1.27 (m, 5H),1.51 (dt, J = 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09(dd, J = 13.1, 8.7 Hz, 1H), 2.40 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H),2.90 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H),4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H),6.84 (q, J = 6.5 Hz, 1H), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4Hz, 1H) 1ag ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 14.8 Hz, 1H),1.58 (s, 8H), 2.05 (m, 2H), 2.39 (s, 8H), 3.12 (d, J = 11.1 Hz, 2H),3.24 (d, J = 11.2 Hz, 3H), 3.47 (s, 3H), 3.53 (s, 1H), 3.64 (s, 4H),4.11 (s, 2H), 4.96 (s, 1H), 6.42 (d, J = 2.0 Hz, 2H), 6.83 (q, J = 6.6Hz, 2H), 7.33 (q, J = 9.0 Hz, 2H), 7.47 (t, J = 6.1 Hz, 2H), 7.65 (m,6H), 7.79 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 2.0 Hz, 2H) 1ah ¹H NMR (400MHz, MeOH-d4): δ ppm 1.29 (d, J = 10.2 Hz, 1H), 1.57 (t, J = 5.3 Hz,5H), 2.04 (dd, J = 13.2, 6.9 Hz, 1H), 2.34 (m, 5H), 3.09 (d, J = 11.8Hz, 1H), 3.22 (m, 2H), 3.48 (dd, J = 25.5, 12.5 Hz, 3H), 3.64 (s, 3H),4.06 (t, J = 7.9 Hz, 1H), 4.83 (s, 2H), 4.93 (s, 1H), 5.74 (s, 1H), 6.41(d, J = 2.4 Hz, 1H), 6.81 (q, J = 6.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H),7.65 (m, 3H), 7.76 (m, 3H), 7.98 (d, J = 2.3 Hz, 1H) 1ai ¹H NMR (400MHz, MeOH-d4): δ ppm 0.91 (tt, J = 8.8, 4.7 Hz, 1H), 1.32 (m, 3H), 1.58(h, J = 5.2, 4.4 Hz, 8H), 1.99 (m, 2H), 2.25 (dd, J = 13.4, 9.0 Hz, 2H),2.40 (s, 6H), 3.03 (d, J = 11.5 Hz, 2H), 3.18 (d, J = 11.5 Hz, 2H), 3.48(ddt, J = 21.1, 13.0, 5.9 Hz, 5H), 3.62 (dt, J = 11.3, 6.3 Hz, 4H), 3.98(t, J = 7.9 Hz, 2H), 5.73 (s, 2H), 6.44 (d, J = 2.4 Hz, 2H), 6.90 (q, J= 6.6 Hz, 2H), 7.86 (m, 6H), 8.04 (d, J = 2.4 Hz, 2H), 9.15 (d, J = 11.9Hz, 6H) 1ak ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.67 (dt, J =11.3, 5.3 Hz, 4H), 2.08 (dd, J = 13.6, 8.1 Hz, 1H), 2.40 (m, 4H), 3.25(q, J = 11.8, 9.3 Hz, 3H), 3.67 (m, 4H), 4.43 (t, J = 8.5 Hz, 1H), 6.44(d, J = 2.4 Hz, 1H), 6.95 (q, J = 6.3 Hz, 1H), 7.77 (dt, J = 5.4, 1.8Hz, 2H), 7.86 (d, J = 1.4 Hz, 2H), 7.96 (m, 1H), 8.05 (d, J = 2.4 Hz,2H) 1al ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.44 (t, J = 7.0Hz, 3H), 1.57 (t, J = 5.6 Hz, 4H), 2.02 (dd, J = 13.4, 7.0 Hz, 1H), 2.28(dd, J = 13.3, 9.1 Hz, 1H), 2.39 (s, 3H), 3.06 (d, J = 11.6 Hz, 1H),3.21 (d, J = 11.6 Hz, 1H), 3.47 (dd, J = 22.4, 13.7 Hz, 3H), 3.65 (dd, J= 13.8, 6.9 Hz, 2H), 4.03 (t, J = 8.1 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H),4.93 (s, 2H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 7.57 (m, 2H), 7.73 (m, 3H), 7.98 (d,J = 2.4 Hz, 1H) 1am ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.7Hz, 2H), 1.55 (m, 4H), 1.92 (dd, J = 13.4, 7.2 Hz, 1H), 2.19 (t, J =10.6 Hz, 1H), 2.40 (s, 3H), 2.88 (d, J = 11.4 Hz, 1H), 3.10 (d, J = 11.5Hz, 1H), 3.47 (dd, J = 22.2, 15.6 Hz, 3H), 3.64 (s, 3H), 3.85 (t, J =8.1 Hz, 1H), 5.74 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6Hz, 1H), 7.69 (m, 3H), 7.82 (m, 2H), 7.99 (m, 3H) 1an ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.17 (t, J = 7.0 Hz, 1H), 1.29 (m, 1H), 1.57 (d, J = 5.9Hz, 4H), 2.00 (dd, J = 13.4, 7.0 Hz, 1H), 2.26 (dd, J = 13.1, 9.4 Hz,1H), 2.38 (d, J = 9.1 Hz, 6H), 3.03 (d, J = 11.6 Hz, 1H), 3.18 (d, J =11.5 Hz, 1H), 3.47 (ddt, J = 20.8, 13.2, 6.0 Hz, 2H), 3.62 (h, J = 7.1,6.4 Hz, 3H), 4.00 (t, J = 7.9 Hz, 1H), 4.89 (s, 9H), 5.74 (s, 1H), 6.41(d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.9, 6.4 Hz, 1H), 7.21 (s, 1H), 7.40(s, 1H), 7.45 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.68 (dd, J = 8.0, 1.8Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H) 1ao ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.28 (m, 2H), 1.55 (q, J = 7.5, 5.1 Hz, 4H),1.94 (dd, J = 13.2, 6.9 Hz, 1H), 2.21 (dd, J = 13.1, 8.9 Hz, 1H), 2.39(s, 3H), 2.94 (d, J = 11.5 Hz, 1H), 3.12 (d, J = 11.2 Hz, 1H), 3.46(ddt, J = 20.2, 13.0, 5.9 Hz, 2H), 3.63 (dd, J = 13.7, 6.1 Hz, 2H), 3.90(t, J = 8.0 Hz, 1H), 4.85 (d, J = 9.0 Hz, 1H), 5.73 (s, 1H), 6.42 (d, J= 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.57 (m, 4H), 7.77 (m, 2H),8.00 (d, J = 2.4 Hz, 1H) 1ap ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J= 11.9 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.59 (t, J = 5.7 Hz, 4H), 2.05(dd, J = 13.4, 7.2 Hz, 1H), 2.39 (s, 4H), 3.12 (d, J = 11.6 Hz, 1H),3.24 (d, J = 11.7 Hz, 1H), 3.51 (ddt, J = 25.1, 13.2, 5.8 Hz, 2H), 3.67(dd, J = 13.8, 5.7 Hz, 2H), 4.10 (dq, J = 14.0, 7.7, 7.0 Hz, 3H), 6.41(d, J = 2.3 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H), 6.93 (dd, J = 8.2, 2.5Hz, 1H), 7.19 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 1.8 Hz,1H), 7.75 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H) 1aq ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.89 (t, J = 7.2 Hz, 1H), 1.28 (s, 4H), 1.58 (t, J = 5.6Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz, 1H), 2.29 (d, J = 1.8 Hz, 4H), 2.39(s, 3H), 3.10 (d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.5 Hz, 1H), 3.49(ddt, J = 21.1, 12.9, 5.8 Hz, 3H), 3.68 (ddt, J = 18.9, 12.4, 6.2 Hz,3H), 4.07 (m, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.80 (q, J =6.5 Hz, 1H), 7.37 (m, 3H), 7.63 (d, J = 1.8 Hz, 1H), 7.76 (m, 2H), 7.98(d, J = 2.3 Hz, 1H) 1ar ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J =5.8 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz, 1H), 2.25 (dd, J = 13.3, 9.1Hz, 1H), 2.39 (s, 3H), 3.00 (d, J = 11.3 Hz, 1H), 3.17 (d, J = 11.5 Hz,1H), 3.31 (d, J = 2.4 Hz, 4H), 3.49 (m, 2H), 3.65 (dd, J = 13.8, 6.6 Hz,2H), 3.97 (t, J = 8.1 Hz, 1H), 5.74 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H),6.83 (q, J = 6.6 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H), 7.65 (m, 2H), 7.73(dd, J = 8.2, 1.9 Hz, 1H), 7.82 (m, 2H), 8.00 (d, J = 2.3 Hz, 1H) 1as ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.60 (m, 4H), 2.05 (dd, J =13.4, 7.1 Hz, 1H), 2.32 (dd, J = 13.4, 9.1 Hz, 1H), 2.40 (s, 3H), 3.12(d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.51 (dq, J = 24.6,7.3, 6.5 Hz, 2H), 3.66 (dt, J = 11.7, 6.2 Hz, 2H), 4.11 (dd, J = 9.1,7.1 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.83 (q, J = 6.3 Hz, 1H), 7.32(m, 1H), 7.58 (dd, J = 15.5, 7.5 Hz, 2H), 7.69 (m, 2H), 7.80 (m, 2H),8.01 (d, J = 2.3 Hz, 1H) 1at ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s,1H), 1.57 (m, 4H), 1.97 (dd, J = 13.1, 6.8 Hz, 1H), 2.23 (m, 2H), 2.37(d, J = 18.2 Hz, 9H), 2.98 (d, J = 11.6 Hz, 1H), 3.15 (d, J = 11.5 Hz,1H), 3.48 (ddt, J = 20.5, 13.0, 5.8 Hz, 2H), 3.65 (dd, J = 13.4, 5.8 Hz,2H), 3.94 (dd, J = 9.1, 7.1 Hz, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz,1H), 6.78 (q, J = 6.6 Hz, 1H), 7.03 (s, 1H), 7.27 (d, J = 1.6 Hz, 2H),7.59 (d, J = 1.8 Hz, 1H), 7.73 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H) 1au ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.4 Hz, 2H), 1.60 (t, J = 5.7Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, 1H), 2.39 (s, 4H), 3.13 (d, J =11.7 Hz, 1H), 3.25 (d, J = 11.7 Hz, 1H), 3.52 (m, 2H), 3.67 (dt, J =12.0, 6.4 Hz, 2H), 4.14 (dd, J = 9.1, 7.2 Hz, 1H), 4.91 (s, 1H), 6.42(d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.36 (dt, J = 10.4, 8.4Hz, 1H), 7.51 (ddt, J = 8.1, 3.9, 1.6 Hz, 1H), 7.65 (m, 2H), 7.77 (m,2H), 7.99 (d, J = 2.3 Hz, 1H) 1av ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57(dt, J = 6.7, 3.0 Hz, 4H), 1.98 (dd, J = 13.3, 7.0 Hz, 1H), 2.24 (dd, J= 13.4, 9.2 Hz, 1H), 2.40 (s, 3H), 2.99 (d, J = 11.5 Hz, 1H), 3.16 (d, J= 11.5 Hz, 1H), 3.48 (ddt, J = 20.5, 13.2, 5.9 Hz, 2H), 3.65 (dq, J =11.1, 5.0 Hz, 2H), 3.95 (t, J = 8.2 Hz, 1H), 5.74 (s, 1H), 6.42 (d, J =2.4 Hz, 1H), 6.84 (q, J = 6.6 Hz, 1H), 6.99 (tt, J = 9.0, 2.3 Hz, 1H),7.35 (m, 2H), 7.68 (d, J = 1.9 Hz, 1H), 7.79 (m, 2H), 8.02 (d, J = 2.4Hz, 1H) 1aw ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 1.30 (d, J =13.3 Hz, 2H), 1.51 (q, J = 6.5, 5.7 Hz, 5H), 1.77 (dd, J = 13.0, 6.9 Hz,1H), 2.05 (dd, J = 13.0, 8.9 Hz, 1H), 2.40 (s, 3H), 2.62 (d, J = 11.0Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 3.42 (d, J = 14.2 Hz, 2H), 3.49 (s,1H), 3.62 (dt, J = 16.7, 6.6 Hz, 3H), 5.72 (s, 1H), 6.42 (d, J = 2.4 Hz,1H), 6.83 (q, J = 6.6 Hz, 1H), 7.44 (m, 1H), 7.69 (d, J = 1.9 Hz, 1H),7.81 (m, 2H), 8.01 (m, 3H) 1ax ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m,2H), 1.32 (m, 13H), 1.57 (t, J = 5.4 Hz, 4H), 2.01 (m, 1H), 2.29 (dd, J= 13.4, 9.2 Hz, 1H), 2.39 (s, 3H), 2.80 (s, 1H), 3.07 (d, J = 11.6 Hz,1H), 3.17 (s, 1H), 3.50 (m, 2H), 3.66 (d, J = 13.8 Hz, 2H), 4.03 (t, J =8.1 Hz, 1H), 4.65 (p, J = 6.1 Hz, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.4Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.16 (t, J = 8.6 Hz, 1H), 7.45 (m,2H), 7.61 (d, J = 1.8 Hz, 1H), 7.74 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H)1ay ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 2H), 1.28 (s, 2H), 1.39(t, J = 7.0 Hz, 3H), 1.59 (d, J = 5.6 Hz, 4H), 2.04 (dd, J = 13.5, 7.1Hz, 1H), 2.39 (s, 4H), 3.10 (d, J = 11.7 Hz, 1H), 3.24 (m, 1H), 3.49(ddt, J = 25.3, 13.1, 5.9 Hz, 2H), 3.66 (dq, J = 12.1, 5.6 Hz, 2H), 4.07(dq, J = 12.7, 7.2 Hz, 3H), 5.75 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.71(dt, J = 10.8, 2.2 Hz, 1H), 6.80 (p, J = 6.6 Hz, 1H), 7.01 (m, 2H), 7.63(d, J = 1.8 Hz, 1H), 7.76 (m, 2H), 8.00 (d, J = 2.4 Hz, 1H) 1az ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.90 (m, 1H), 1.36 (s, 13H), 1.59 (m, 4H),2.05 (dd, J = 13.4, 6.9 Hz, 1H), 2.33 (dt, J = 13.7, 6.0 Hz, 1H), 2.40(s, 3H), 3.12 (d, J = 11.4 Hz, 1H), 3.24 (d, J = 12.1 Hz, 1H), 3.40 (s,1H), 3.53 (d, J = 14.7 Hz, 1H), 3.68 (d, J = 13.4 Hz, 2H), 4.10 (s, 1H),4.76 (m, 5H), 4.83 (s, 2H), 5.01 (s, 1H), 6.42 (d, J = 2.2 Hz, 1H), 6.77(q, J = 6.6 Hz, 1H), 7.42 (m, 3H), 7.65 (m, 4H), 7.76 (m, 2H), 7.98 (d,J = 2.3 Hz, 1H) 1ba ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 12.1Hz, 3H), 1.59 (t, J = 5.2 Hz, 4H), 2.05 (dd, J = 13.4, 7.0 Hz, 1H), 2.34(m, 7H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.8 Hz, 1H), 3.51 (m,2H), 3.68 (dt, J = 13.1, 6.3 Hz, 2H), 4.09 (dd, J = 9.2, 6.9 Hz, 1H),6.41 (d, J = 2.3 Hz, 1H), 6.79 (q, J = 6.7 Hz, 1H), 7.11 (t, J = 9.1 Hz,1H), 7.55 (m, 3H), 7.74 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H) 1bb ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 6.9 Hz, 6H), 1.59 (t, J = 5.6 Hz,4H), 2.05 (dd, J = 13.4, 6.9 Hz, 1H), 2.32 (dd, J = 13.4, 8.9 Hz, 1H),2.40 (s, 3H), 2.96 (h, J = 6.8 Hz, 1H), 3.12 (d, J = 11.8 Hz, 1H), 3.24(d, J = 11.7 Hz, 1H), 3.51 (m, 2H), 3.67 (m, 2H), 4.10 (t, J = 8.3 Hz,1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.5 Hz, 1H), 7.27 (m, 1H),7.37 (t, J = 7.7 Hz, 1H), 7.48 (m, 2H), 7.62 (d, J = 1.8 Hz, 1H), 7.76(m, 2H), 7.98 (d, J = 2.4 Hz, 1H) 1bc ¹H NMR (400 MHz, MeOH-d4): δ ppm0.89 (m, 1H), 1.29 (m, 9H), 1.55 (d, J = 5.8 Hz, 4H), 1.99 (m, 1H), 2.26(dd, J = 13.4, 9.1 Hz, 1H), 2.39 (s, 3H), 3.04 (d, J = 11.6 Hz, 1H),3.17 (d, J = 11.6 Hz, 1H), 3.47 (ddt, J = 20.9, 13.0, 5.9 Hz, 2H), 3.62(dq, J = 11.5, 5.7 Hz, 2H), 4.01 (m, 1H), 4.64 (hept, J = 5.9 Hz, 1H),5.74 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H), 6.91(dd, J = 8.1, 2.4 Hz, 1H), 7.16 (ddd, J = 8.5, 5.3, 1.7 Hz, 2H), 7.32(t, J = 7.9 Hz, 1H), 7.64 (m, 3H), 7.77 (d, J = 8.3 Hz, 1H), 7.97 (d, J= 2.4 Hz, 1H) 1bd ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59(d, J = 5.6 Hz, 4H), 2.05 (dd, J = 13.4, 7.0 Hz, 1H), 2.31 (dd, J =13.4, 9.3 Hz, 1H), 2.41 (d, J = 11.1 Hz, 6H), 3.11 (d, J = 11.7 Hz, 1H),3.24 (d, J = 11.7 Hz, 1H), 3.49 (ddd, J = 27.1, 12.8, 5.9 Hz, 2H), 3.66(dq, J = 13.8, 6.0 Hz, 2H), 4.07 (dd, J = 9.2, 7.0 Hz, 1H), 5.75 (s,1H), 6.42 (d, J = 2.4 Hz, 1H), 6.80 (q, J = 6.6 Hz, 1H), 7.45 (m, 2H),7.63 (dd, J = 7.2, 2.0 Hz, 2H), 7.76 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H)1be ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.9 Hz, 4H), 1.59 (t,J = 5.8 Hz, 7H), 2.05 (dd, J = 13.3, 7.0 Hz, 2H), 2.31 (dd, J = 13.4,9.2 Hz, 2H), 2.40 (s, 5H), 3.11 (d, J = 11.7 Hz, 2H), 3.24 (m, 4H), 3.50(dq, J = 23.7, 7.4, 6.5 Hz, 4H), 3.67 (dq, J = 13.1, 6.4 Hz, 4H), 4.09(t, J = 8.1 Hz, 2H), 4.84 (s, 1H), 4.93 (s, 1H), 6.42 (d, J = 2.3 Hz,2H), 6.84 (q, J = 6.5 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.74 (s, 2H),7.88 (m, 7H), 7.99 (d, J = 2.4 Hz, 2H), 8.19 (t, J = 1.9 Hz, 2H) 1bf ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 5.7 Hz, 4H), 1.99 (dd, J =13.3, 7.0 Hz, 1H), 2.25 (dd, J = 13.3, 9.1 Hz, 1H), 2.41 (s, 3H), 3.01(d, J = 11.6 Hz, 1H), 3.17 (d, J = 11.5 Hz, 1H), 3.48 (dq, J = 23.5,7.0, 6.5 Hz, 2H), 3.64 (dd, J = 13.0, 5.8 Hz, 2H), 3.97 (dd, J = 9.0,7.1 Hz, 1H), 5.73 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.87 (q, J = 6.6Hz, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.88 (m, 2H), 8.00 (s, 1H), 8.07 (d,J = 2.3 Hz, 1H), 8.29 (s, 2H) 1bg ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28(s, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.64 (q, J = 5.8 Hz, 4H), 2.08 (dd, J= 13.5, 7.7 Hz, 1H), 2.40 (s, 4H), 3.23 (m, 2H), 3.64 (m, 4H), 4.18 (q,J = 7.0 Hz, 2H), 4.32 (t, J = 8.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H),6.83 (q, J = 6.4 Hz, 1H), 7.20 (m, 2H), 7.36 (dd, J = 8.0, 2.1 Hz, 1H),7.65 (d, J = 1.6 Hz, 1H), 7.77 (m, 2H), 7.99 (d, J = 2.4 Hz, 1H) 1bh ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59 (d, J = 5.4 Hz, 4H),2.04 (dd, J = 13.4, 7.0 Hz, 1H), 2.29 (m, 2H), 2.41 (d, J = 9.6 Hz, 9H),3.10 (d, J = 11.7 Hz, 1H), 3.24 (m, 1H), 3.49 (ddt, J = 20.7, 13.0, 6.0Hz, 2H), 3.65 (dt, J = 13.2, 7.2 Hz, 2H), 4.06 (dd, J = 9.2, 7.1 Hz,1H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H),7.45 (s, 2H), 7.62 (d, J = 1.8 Hz, 1H), 7.75 (m, 2H), 7.98 (d, J = 2.4Hz, 1H) 1bi ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (m, 4H), 1.99 (dd, J =13.4, 7.1 Hz, 1H), 2.26 (dd, J = 13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 3.02(d, J = 11.6 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 3.48 (dq, J = 23.5,7.1, 6.6 Hz, 2H), 3.64 (dq, J = 11.4, 5.5 Hz, 2H), 3.99 (dd, J = 9.2,7.0 Hz, 1H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.85 (q, J = 6.6Hz, 1H), 7.46 (t, J = 1.9 Hz, 1H), 7.66 (t, J = 1.8 Hz, 3H), 7.73 (dd, J= 8.3, 2.0 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H)1bj ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 1H), 1.34 (s, 10H), 1.61(t, J = 5.9 Hz, 4H), 2.06 (dd, J = 13.5, 7.3 Hz, 1H), 2.39 (m, 7H), 3.14(d, J = 11.6 Hz, 1H), 3.25 (m, 1H), 3.55 (m, 2H), 3.68 (s, 2H), 4.18(dd, J = 9.0, 7.3 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.5Hz, 1H), 7.28 (m, 2H), 7.45 (t, J = 1.7 Hz, 1H), 7.60 (d, J = 1.8 Hz,1H), 7.75 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H) 1bk ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (s, 2H), 1.58 (t, J = 5.5 Hz, 4H), 2.04 (dd, J =13.3, 6.9 Hz, 1H), 2.30 (dd, J = 13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 3.09(d, J = 11.7 Hz, 1H), 3.23 (d, J = 12.2 Hz, 1H), 3.51 (m, 2H), 3.66 (dd,J = 13.9, 6.6 Hz, 2H), 4.05 (t, J = 8.2 Hz, 1H), 4.62 (s, 1H), 5.75 (s,1H), 6.42 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.5 Hz, 1H), 7.43 (m, 2H),7.63 (m, 2H), 7.75 (m, 3H), 8.00 (d, J = 2.3 Hz, 1H) 1bl ¹H NMR (400MHz, MeOH-d4): δ ppm 1.57 (t, J = 5.6 Hz, 4H), 2.00 (dd, J = 13.5, 7.0Hz, 1H), 2.26 (dd, J = 13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 3.03 (d, J =11.6 Hz, 1H), 3.18 (d, J = 11.5 Hz, 1H), 3.47 (ddd, J = 20.9, 14.0, 6.5Hz, 2H), 3.64 (t, J = 7.4 Hz, 2H), 3.99 (dd, J = 9.1, 7.1 Hz, 1H), 5.74(s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.86 (q, J = 6.6 Hz, 1H), 7.81 (m,5H), 7.98 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H) 1bm ¹H NMR (400MHz, MeOH-d4): δ 1.54 (d, J = 2.93 Hz, 4 H), 1.82-1.99 (m, 1 H),2.09-2.24 (m, 1 H), 2.40 (s, 3 H), 2.79-2.93 (m, 1 H), 2.99-3.14 (m, 1H), 3.37-3.55 (m, 2 H), 3.56-3.72 (m, 2 H), 3.82 (s, 4 H), 5.74 (s, 1H), 6.41 (d, J = 2.15 Hz, 1 H), 6.70-6.84 (m, 1 H), 6.99 (d, J = 8.79Hz, 2 H), 7.50-7.63 (m, 3 H), 7.64-7.71 (m, 1 H), 7.71-7.80 (m, 1 H),7.95 (d, J = 2.15 Hz, 1 H) 1bn ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m,1H), 1.28 (s, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.58 (t, J = 5.2 Hz, 4H),2.05 (dd, J = 13.4, 7.0 Hz, 1H), 2.31 (dd, J = 13.4, 9.0 Hz, 1H), 2.39(s, 3H), 3.11 (d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.51 (m,2H), 3.67 (m, 2H), 4.13 (m, 3H), 4.63 (s, 1H), 5.75 (s, 1H), 6.41 (d, J= 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 7.45(m, 2H), 7.60 (d, J = 1.8 Hz, 1H), 7.73 (m, 2H), 7.97 (d, J = 2.4 Hz,1H) 1bo ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 8.3 Hz, 1H), 1.59(t, J = 5.3 Hz, 4H), 2.05 (dd, J = 13.5, 7.0 Hz, 1H), 2.32 (dd, J =13.6, 9.2 Hz, 1H), 2.39 (s, 3H), 3.12 (d, J = 11.6 Hz, 1H), 3.25 (m,1H), 3.49 (ddd, J = 24.6, 12.8, 5.8 Hz, 2H), 3.66 (dq, J = 12.7, 6.0 Hz,2H), 4.09 (t, J = 8.1 Hz, 1H), 5.76 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H),6.85 (q, J = 6.6 Hz, 1H), 7.54 (m, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.78(m, 2H), 8.01 (d, J = 2.3 Hz, 1H) 1bp ¹H NMR (400 MHz, MeOH-d4): δ ppm1.29 (d, J = 8.6 Hz, 1H), 1.59 (d, J = 5.9 Hz, 4H), 2.05 (dd, J = 13.5,7.3 Hz, 1H), 2.39 (m, 7H), 3.13 (d, J = 11.6 Hz, 1H), 3.24 (m, 2H), 3.52(dq, J = 25.3, 6.3 Hz, 2H), 3.68 (dd, J = 13.7, 5.9 Hz, 2H), 4.16 (m,1H), 6.42 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.5 Hz, 1H), 7.37 (d, J =7.9 Hz, 1H), 7.51 (dd, J = 7.9, 2.0 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H),7.73 (m, 3H), 7.98 (d, J = 2.4 Hz, 1H) 1bq ¹H NMR (400 MHz, MeOH-d4): δppm 1.29 (d, J = 8.0 Hz, 1H), 1.59 (m, 4H), 2.05 (dd, J = 13.4, 7.0 Hz,1H), 2.38 (d, J = 13.7 Hz, 7H), 3.13 (d, J = 11.7 Hz, 1H), 3.25 (d, J =11.6 Hz, 1H), 3.53 (dt, J = 31.7, 10.3 Hz, 2H), 3.67 (dd, J = 13.5, 7.0Hz, 2H), 4.15 (m, 1H), 4.89 (s, 17H), 6.42 (d, J = 2.4 Hz, 1H), 6.82 (q,J = 6.6 Hz, 1H), 7.32 (m, 1H), 7.61 (m, 4H), 7.76 (m, 2H), 7.99 (d, J =2.3 Hz, 1H) 1br ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (s, 1H), 1.29 (m,8H), 1.60 (d, J = 7.7 Hz, 4H), 2.02 (m, 2H), 2.39 (s, 4H), 3.14 (d, J =11.6 Hz, 1H), 3.25 (d, J = 11.4 Hz, 1H), 3.51 (m, 2H), 3.66 (dd, J =13.6, 6.6 Hz, 2H), 4.11 (dt, J = 21.0, 7.6 Hz, 1H), 4.65 (h, J = 6.0 Hz,1H), 6.42 (d, J = 2.3 Hz, 1H), 6.69 (dt, J = 10.9, 2.2 Hz, 1H), 6.82 (q,J = 6.3 Hz, 1H), 6.99 (m, 2H), 7.61 (d, J = 1.8 Hz, 1H), 7.71 (m, 1H),7.78 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H) 1bs ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.09 (s, 1H), 0.90 (q, J = 8.4, 7.7 Hz, 1H), 1.29 (d, J= 8.6 Hz, 3H), 1.59 (d, J = 5.7 Hz, 5H), 2.05 (dd, J = 13.5, 6.9 Hz,1H), 2.31 (dd, J = 13.6, 9.4 Hz, 1H), 2.40 (s, 3H), 3.13 (d, J = 11.6Hz, 1H), 3.25 (m, 1H), 3.61 (m, 5H), 4.08 (m, 1H), 5.74 (s, 1H), 6.43(d, J = 2.4 Hz, 1H), 6.85 (q, J = 6.7 Hz, 1H), 7.24 (dt, J = 8.5, 2.1Hz, 1H), 7.45 (dt, J = 9.6, 2.0 Hz, 1H), 7.58 (t, J = 1.7 Hz, 1H), 7.68(d, J = 1.9 Hz, 1H), 7.79 (m, 2H), 8.02 (d, J = 2.3 Hz, 1H) 1bt ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 1.7 Hz, 1H), 1.58 (t, J = 5.7 Hz,4H), 2.03 (dd, J = 13.4, 7.0 Hz, 1H), 2.29 (dd, J = 13.4, 9.2 Hz, 1H),2.40 (s, 3H), 3.07 (d, J = 11.6 Hz, 1H), 3.22 (d, J = 11.6 Hz, 1H), 3.49(m, 2H), 3.65 (dd, J = 13.0, 6.7 Hz, 2H), 4.04 (dd, J = 9.2, 7.0 Hz,1H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.6 Hz, 1H),7.77 (m, 5H), 7.92 (dd, J = 8.4, 2.2 Hz, 1H), 8.04 (dd, J = 14.2, 2.3Hz, 2H) 1bu ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (d, J = 5.4 Hz, 4H),2.05 (dd, J = 13.5, 7.1 Hz, 1H), 2.40 (s, 4H), 3.11 (d, J = 11.7 Hz,1H), 3.24 (d, J = 11.7 Hz, 1H), 3.49 (ddt, J = 21.1, 13.3, 6.0 Hz, 2H),3.67 (dt, J = 12.9, 6.1 Hz, 2H), 4.07 (dd, J = 9.2, 7.1 Hz, 1H), 5.74(s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.86 (q, J = 6.6 Hz, 1H), 7.50 (m,1H), 7.80 (m, 5H), 8.04 (d, J = 2.4 Hz, 1H) 1bv ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.35 (d, J = 6.0 Hz, 7H), 1.55 (d, J = 5.9 Hz, 4H), 1.98(dd, J = 13.3, 7.0 Hz, 1H), 2.25 (dd, J = 13.3, 9.1 Hz, 1H), 2.39 (s,2H), 3.01 (d, J = 11.5 Hz, 1H), 3.17 (d, J = 11.6 Hz, 1H), 3.47 (ddt, J= 20.8, 13.0, 6.0 Hz, 2H), 3.64 (dd, J = 13.9, 6.3 Hz, 2H), 3.98 (dd, J= 9.2, 7.1 Hz, 1H), 4.67 (p, J = 6.1 Hz, 1H), 4.89 (s, 11H), 5.74 (s,1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H), 7.13 (d, J =8.7 Hz, 1H), 7.55 (m, 2H), 7.71 (m, 4H), 7.98 (d, J = 2.4 Hz, 1H) 1bw ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.54 (t, J = 5.7 Hz, 4H), 1.95 (dd, J =13.3, 7.0 Hz, 1H), 2.22 (dd, J = 13.3, 9.0 Hz, 1H), 2.41 (s, 3H), 2.95(d, J = 11.5 Hz, 1H), 3.13 (d, J = 11.4 Hz, 1H), 3.47 (ddt, J = 19.9,12.9, 5.9 Hz, 2H), 3.64 (dd, J = 13.3, 6.4 Hz, 2H), 3.94 (t, J = 8.1 Hz,1H), 4.91 (s, 10H), 5.77 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.83 (q, J =6.6 Hz, 1H), 7.49 (m, 2H), 7.83 (m, 7H), 8.01 (d, J = 2.4 Hz, 1H), 8.13(d, J = 1.9 Hz, 1H) 1bx ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (m, 4H),2.05 (dd, J = 13.5, 7.2 Hz, 1H), 2.39 (s, 4H), 3.12 (d, J = 11.7 Hz,1H), 3.24 (d, J = 11.8 Hz, 1H), 3.51 (m, 2H), 3.67 (dd, J = 13.7, 6.2Hz, 2H), 4.13 (dd, J = 9.1, 7.2 Hz, 1H), 5.19 (s, 2H), 6.41 (d, J = 2.3Hz, 1H), 6.79 (q, J = 6.5 Hz, 1H), 7.21 (t, J = 8.6 Hz, 1H), 7.42 (m,7H), 7.60 (d, J = 1.8 Hz, 1H), 7.72 (m, 2H), 7.97 (d, J = 2.3 Hz, 1H)1by ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (dd, J = 6.1, 1.6 Hz, 6H),1.58 (t, J = 5.2 Hz, 4H), 2.04 (dd, J = 13.5, 7.1 Hz, 1H), 2.22 (s, 3H),2.35 (m, 4H), 3.10 (d, J = 11.8 Hz, 1H), 3.23 (d, J = 11.8 Hz, 1H), 3.49(ddt, J = 20.8, 13.6, 5.9 Hz, 2H), 3.66 (dd, J = 13.6, 6.9 Hz, 2H), 4.07(dd, J = 9.2, 7.1 Hz, 1H), 4.63 (p, J = 6.1 Hz, 1H), 5.76 (s, 1H), 6.41(d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.7 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H),7.45 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 1.8 Hz, 1H), 7.71 (m, 2H), 7.96(d, J = 2.3 Hz, 1H) 1bz ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J =7.4 Hz, 3H), 1.29 (m, 1H), 1.58 (d, J = 5.9 Hz, 4H), 1.83 (h, J = 7.1Hz, 2H), 2.02 (dd, J = 13.4, 6.9 Hz, 1H), 2.29 (dd, J = 13.3, 9.1 Hz,1H), 2.39 (s, 3H), 3.08 (d, J = 11.6 Hz, 1H), 3.21 (d, J = 11.5 Hz, 1H),3.48 (ddd, J = 21.8, 12.6, 5.8 Hz, 2H), 3.65 (dd, J = 13.6, 7.3 Hz, 2H),4.04 (q, J = 7.1, 6.4 Hz, 3H), 4.97 (s, 1H), 5.75 (s, 1H), 6.41 (d, J =2.3 Hz, 1H), 6.78 (q, J = 6.5 Hz, 1H), 7.14 (t, J = 8.6 Hz, 1H), 7.44(m, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.72 (m, 2H), 7.98 (d, J = 2.3 Hz,1H) 1ca ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.99 (t, J = 7.4 Hz, 3H), 1.53(m, 6H), 1.79 (dq, J = 8.6, 6.5 Hz, 2H), 1.93 (dd, J = 13.2, 7.0 Hz,1H), 2.20 (dd, J = 13.3, 9.1 Hz, 1H), 2.39 (s, 3H), 2.91 (d, J = 11.4Hz, 1H), 3.11 (d, J = 11.4 Hz, 1H), 3.47 (ddt, J = 20.0, 13.0, 5.9 Hz,2H), 3.64 (dd, J = 13.8, 5.7 Hz, 2H), 3.88 (t, J = 8.0 Hz, 1H), 4.07 (t,J = 6.4 Hz, 2H), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.78 (q, J =6.7 Hz, 1H), 7.14 (t, J = 8.6 Hz, 1H), 7.43 (m, 2H), 7.59 (d, J = 1.9Hz, 1H), 7.71 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H) 1cb ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.89 (s, 1H), 1.28 (s, 1H), 1.62 (d, J = 6.2 Hz, 8H),2.06 (dd, J = 13.3, 7.3 Hz, 2H), 2.41 (s, 8H), 2.65 (s, 5H), 3.15 (d, J= 12.0 Hz, 2H), 3.25 (m, 2H), 3.52 (s, 3H), 3.58 (s, 2H), 3.70 (d, J =13.3 Hz, 4H), 4.21 (t, J = 8.4 Hz, 2H), 5.89 (s, 1H), 6.00 (m, 1H), 6.44(d, J = 2.3 Hz, 2H), 6.89 (q, J = 6.4 Hz, 2H), 7.80 (m, 10H), 8.04 (d, J= 2.3 Hz, 2H), 8.12 (t, J = 7.9 Hz, 2H) 1cc ¹H NMR (400 MHz, MeOH-d4): δppm 1.29 (d, J = 6.2 Hz, 1H), 1.57 (m, 4H), 1.99 (dd, J = 13.4, 7.0 Hz,1H), 2.25 (dd, J = 13.4, 9.1 Hz, 1H), 2.40 (s, 3H), 3.01 (d, J = 11.6Hz, 1H), 3.15 (m, 4H), 3.32 (s, 1H), 3.48 (ddt, J = 20.3, 12.8, 5.9 Hz,2H), 3.65 (dd, J = 13.9, 7.0 Hz, 2H), 3.97 (dd, J = 9.1, 7.0 Hz, 1H),4.89 (m, 2H), 5.75 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.85 (q, J = 6.6Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.84 (m, 2H), 7.94 (d, J = 8.5 Hz,2H), 8.03 (m, 3H) 1cd ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4Hz, 3H), 1.51 (q, J = 6.5, 5.7 Hz, 4H), 1.80 (h, J = 6.7, 6.1 Hz, 3H),1.89 (d, J = 1.5 Hz, 1H), 2.07 (dd, J = 12.7, 9.2 Hz, 1H), 2.39 (s, 3H),2.67 (d, J = 11.2 Hz, 1H), 2.94 (t, J = 11.8 Hz, 1H), 3.40 (m, 3H), 3.64(m, 3H), 3.96 (t, J = 6.4 Hz, 2H), 4.89 (m, 1H), 5.75 (s, 1H), 6.41 (d,J = 2.3 Hz, 1H), 6.75 (m, 1H), 6.99 (m, 2H), 7.59 (dd, J = 9.0, 2.0 Hz,3H), 7.71 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H) 1ce ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.30 (d, J = 16.9 Hz, 4H), 1.57 (s, 5H), 2.02 (m, 1H),2.27 (dd, J = 13.3, 8.8 Hz, 1H), 2.40 (s, 3H), 2.60 (m, 6H), 3.06 (d, J= 11.4 Hz, 1H), 3.20 (d, J = 11.3 Hz, 1H), 3.34 (s, 1H), 3.48 (s, 3H),3.56 (t, J = 6.7 Hz, 2H), 3.70 (m, 7H), 4.02 (s, 1H), 4.98 (d, J = 6.2Hz, 1H), 5.76 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.5 Hz,1H), 7.71 (s, 1H), 7.80 (m, 4H), 7.93 (d, J = 8.0 Hz, 2H), 8.01 (d, J =2.3 Hz, 1H) 1cf ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.90 (t, J = 6.4 Hz,1H), 1.30 (dd, J = 12.6, 4.9 Hz, 6H), 1.55 (m, 5H), 1.93 (dd, J = 13.2,7.0 Hz, 1H), 2.19 (qd, J = 9.4, 3.3 Hz, 1H), 2.40 (s, 3H), 2.92 (d, J =11.4 Hz, 1H), 3.11 (d, J = 11.3 Hz, 1H), 3.48 (m, 2H), 3.65 (dd, J =13.7, 6.3 Hz, 2H), 3.88 (dd, J = 8.9, 7.2 Hz, 1H), 4.87 (d, J = 12.3 Hz,1H), 4.97 (d, J = 12.9 Hz, 2H), 5.75 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H),6.83 (q, J = 6.7 Hz, 1H), 7.73 (s, 1H), 7.84 (m, 4H), 8.00 (m, 3H) 1cg¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (s, 1H), 1.58 (d, J = 5.9 Hz, 4H),2.03 (dd, J = 13.4, 6.9 Hz, 1H), 2.30 (dd, J = 13.3, 9.2 Hz, 1H), 2.40(s, 3H), 3.11 (d, J = 11.7 Hz, 1H), 3.23 (d, J = 11.5 Hz, 1H), 3.48(ddd, J = 28.3, 12.4, 5.7 Hz, 2H), 3.65 (dd, J = 13.7, 7.2 Hz, 2H), 4.07(m, 1H), 5.76 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.5 Hz,1H), 7.70 (d, J = 1.7 Hz, 1H), 7.79 (dt, J = 13.1, 8.1 Hz, 4H), 7.99 (m,3H) 1ch ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.6 Hz, 1H), 1.63(q, J = 5.8 Hz, 5H), 2.07 (dd, J = 13.5, 7.5 Hz, 1H), 2.37 (dd, J =13.5, 9.0 Hz, 1H), 3.04 (s, 3H), 3.15 (d, J = 24.6 Hz, 6H), 3.27 (m,1H), 3.52 (dt, J = 24.6, 8.3 Hz, 2H), 3.65 (m, 2H), 4.23 (t, J = 8.1 Hz,1H), 6.66 (q, J = 7.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.68 (m, 6H)1ci ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (d, J = 5.6 Hz, 4H), 2.03 (dd,J = 13.3, 7.1 Hz, 1H), 2.30 (dd, J = 13.4, 9.2 Hz, 1H), 2.39 (s, 3H),3.09 (d, J = 11.7 Hz, 1H), 3.22 (d, J = 11.7 Hz, 1H), 3.49 (ddd, J =21.1, 12.5, 5.6 Hz, 2H), 3.66 (dd, J = 13.7, 6.7 Hz, 2H), 3.90 (s, 3H),4.06 (dd, J = 9.2, 7.1 Hz, 1H), 5.76 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H),6.78 (q, J = 6.6 Hz, 1H), 7.17 (t, J = 8.9 Hz, 1H), 7.46 (m, 2H), 7.60(d, J = 1.8 Hz, 1H), 7.73 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H) 1cj ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 17.0 Hz, 1H), 1.57 (d, J = 5.5Hz, 4H), 2.01 (dd, J = 13.2, 7.0 Hz, 1H), 2.28 (dd, J = 13.3, 9.0 Hz,1H), 2.40 (s, 3H), 2.79 (s, 2H), 2.91 (s, 2H), 3.07 (d, J = 12.1 Hz,1H), 3.20 (d, J = 11.4 Hz, 1H), 3.49 (m, 4H), 3.65 (dd, J = 13.5, 6.9Hz, 2H), 3.74 (s, 2H), 4.02 (t, J = 8.1 Hz, 1H), 4.99 (s, 1H), 5.76 (s,1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.52 (d, J =7.9 Hz, 2H), 7.76 (m, 5H), 8.01 (d, J = 2.4 Hz, 1H) 1ck ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.30 (d, J = 11.1 Hz, 1H), 1.51 (q, J = 6.8, 6.0 Hz,4H), 1.78 (dd, J = 13.0, 7.0 Hz, 1H), 1.89 (s, 2H), 2.07 (dd, J = 13.1,9.1 Hz, 1H), 2.40 (s, 3H), 2.68 (d, J = 11.1 Hz, 1H), 2.95 (d, J = 11.1Hz, 1H), 3.03 (s, 3H), 3.11 (s, 3H), 3.22 (s, 2H), 3.45 (m, 3H), 3.63(q, J = 7.9, 7.5 Hz, 3H), 5.75 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82(q, J = 6.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.70 (m, 1H), 7.80 (m,4H), 8.01 (d, J = 2.5 Hz, 1H) 1cl ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.04(d, J = 6.7 Hz, 6H), 1.29 (m, 1H), 1.60 (d, J = 6.0 Hz, 5H), 2.05 (ddd,J = 13.7, 7.0, 3.9 Hz, 2H), 2.36 (m, 4H), 3.13 (d, J = 11.9 Hz, 1H),3.24 (d, J = 11.6 Hz, 1H), 3.51 (ddd, J = 25.5, 14.3, 7.1 Hz, 2H), 3.69(d, J = 13.8 Hz, 3H), 3.77 (d, J = 6.4 Hz, 2H), 4.14 (t, J = 8.3 Hz,1H), 4.93 (s, 8H), 6.41 (d, J = 2.3 Hz, 1H), 6.77 (q, J = 6.6 Hz, 1H),6.99 (m, 2H), 7.60 (m, 3H), 7.72 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H) 1cm¹H NMR (400 MHz, MeOH-d4): δ 1.14 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.3Hz, 3H), 1.55 (q, J = 4.8 Hz, 4H), 1.90 (m, 1H), 2.18 (dd, J = 13.2, 9.0Hz, 1H), 2.40 (s, 3H), 2.87 (d, J = 11.4 Hz, 1H), 3.09 (d, J = 11.3 Hz,1H), 3.30 (m, 4H), 3.54 (dddd, J = 37.2, 30.6, 15.1, 5.9 Hz, 6H), 3.84(dd, J = 9.0, 6.9 Hz, 1H), 5.76 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.83(q, J = 6.6 Hz, 1H), 7.48 (m, 2H), 7.70 (d, J = 1.6 Hz, 1H), 7.80 (m,4H), 8.01 (d, J = 2.3 Hz, 1H) 1cn ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.84(s, 3H), 1.06 (s, 10H), 1.30 (m, 1H), 1.56 (t, J = 5.4 Hz, 4H), 2.00(dd, J = 13.4, 6.8 Hz, 1H), 2.27 (dd, J = 13.2, 9.0 Hz, 1H), 2.41 (s,3H), 3.04 (d, J = 11.5 Hz, 1H), 3.19 (d, J = 11.4 Hz, 1H), 3.48 (ddt, J= 20.4, 13.0, 5.9 Hz, 2H), 3.65 (s, 4H), 4.03 (t, J = 8.1 Hz, 1H), 5.77(s, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.79 (q, J = 6.6 Hz, 1H), 6.98 (d, J= 8.4 Hz, 2H), 7.60 (m, 4H), 7.75 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 2.3Hz, 1H) 1co ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 5.8 Hz, 1H),1.55 (t, J = 5.7 Hz, 4H), 1.98 (m, 3H), 2.25 (dd, J = 13.3, 9.2 Hz, 1H),2.39 (s, 3H), 2.80 (t, J = 6.5 Hz, 2H), 3.02 (d, J = 11.6 Hz, 1H), 3.17(d, J = 11.6 Hz, 1H), 3.47 (ddt, J = 20.5, 13.0, 5.9 Hz, 2H), 3.64 (dt,J = 13.8, 5.9 Hz, 2H), 4.00 (dd, J = 9.2, 7.1 Hz, 1H), 4.16 (m, 2H),5.75 (s, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.76 (m, 2H), 7.33 (d, J = 6.5Hz, 2H), 7.54 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 8.3, 1.9 Hz, 1H), 7.71(d, J = 8.3 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H) 1cp ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.59 (t, J = 5.3 Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz,1H), 2.31 (dd, J = 13.4, 9.3 Hz, 1H), 2.42 (s, 3H), 3.11 (d, J = 11.7Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.51 (m, 2H), 3.67 (s, 2H), 4.07(dd, J = 9.3, 7.1 Hz, 1H), 4.89 (s, 1H), 5.78 (s, 1H), 5.99 (m, 1H),6.46 (d, J = 2.3 Hz, 1H), 6.89 (q, J = 6.5 Hz, 1H), 7.91 (m, 2H), 8.00(dd, J = 8.3, 2.0 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 8.34 (m, 3H), 8.55(d, J = 8.9 Hz, 1H), 9.33 (d, J = 5.9 Hz, 1H) 1cq ¹H NMR (400 MHz,MeOH-d4): δ ppm 7.97 (s, 1H), 7.77 (s, 2H), 7.67 (d, J = 15.8 Hz, 2H),7.51 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.42 (s, 1H), 4.69 (s, 2H), 4.14(s, 1H), 3.68 (s, 2H), 3.51 (s, 3H), 3.23 (s, 1H), 3.13 (d, J = 11.6 Hz,1H), 2.38 (d, J = 14.0 Hz, 6H), 2.05 (s, 1H), 1.60 (s, 4H), 1.29 (s, 3H)1cr ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 2H), 7.74 (q, J = 8.3 Hz,4H), 7.62 (s, 2H), 7.46 (d, J = 7.4 Hz, 5H), 6.78 (q, J = 6.7 Hz, 2H),6.41 (s, 2H), 5.75 (s, 2H), 4.65 (s, 3H), 4.07 (t, J = 8.1 Hz, 2H), 3.64(s, 4H), 3.52 (d, J = 6.9 Hz, 1H), 3.46 (d, J = 16.2 Hz, 4H), 3.22 (d, J= 11.8 Hz, 2H), 3.10 (d, J = 11.8 Hz, 2H), 2.38 (d, J = 7.9 Hz, 10H),2.29 (s, 1H), 2.03 (dd, J = 13.4, 7.0 Hz, 2H), 1.58 (d, J = 5.6 Hz, 7H),1.30 (d, J = 13.4 Hz, 5H) 1cs ¹H NMR (400 MHz, MeOH-d4): δ ppm 8.43 (d,J = 2.5 Hz, 1H), 7.99 (q, J = 3.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H),7.72 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 6.83 (dd, J = 20.4, 7.6 Hz, 2H),6.42 (d, J = 2.3 Hz, 1H), 5.74 (s, 1H), 4.35 (q, J = 7.0 Hz, 2H), 3.96(d, J = 8.9 Hz, 1H), 3.64 (s, 3H), 3.48 (dd, J = 25.9, 11.9 Hz, 2H),3.15 (d, J = 11.7 Hz, 1H), 2.99 (d, J = 11.4 Hz, 1H), 2.39 (s, 3H), 2.24(s, 1H), 2.02-1.94 (m, 1H), 1.56 (s, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.28(s, 1H).

Example 1cp:(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 1u) starting with(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4H) 1.91-2.01 (m, 1H)2.18-2.27 (m, 1H) 2.33 (d, J=11.71 Hz, 6H) 2.88-3.00 (m, 1H) 3.08-3.19(m, 1H) 3.38-3.56 (m, 2H) 3.58-3.75 (m, 2H) 3.85-3.98 (m, 1H) 5.65 (s,1H) 6.55-6.70 (m, 1H) 6.92-7.04 (m, 1H) 7.19-7.28 (m, 1H) 7.38-7.46 (m,1H) 7.46-7.53 (m, 1H) 7.72 (s, 1H) 7.83 (s, 2H) 8.22-8.35 (m, 1H) LCMS(MH+): 690.

Example 2:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

A solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(Example 1f) (150 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in anH-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and Theproduct was purified by column chromatography using an Isco Goldreversed phase silica cartridge (100% CH₂Cl₂ to 90:9:1 CH₂Cl₂:MeOH:conc.NH₄OH) to provide (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

Step 2:

Hydrolysis of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateusing the LiOH general method provided the title compound as anoff-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.49-1.69 (m, 4H) 2.00-2.18 (m, 3H)2.21-2.35 (m, 1H) 2.38 (s, 3H) 2.92-3.05 (m, 1H) 3.08 (d, J=0.44 Hz, 2H)3.10-3.18 (m, 2H) 3.25 (d, J=11.71 Hz, 1H) 3.38-3.72 (m, 7H) 4.09 (t,J=7.88 Hz, 1H) 5.69 (s, 1H) 6.41 (d, J=2.29 Hz, 1H) 6.74 (q, J=6.80 Hz,1H) 7.34 (d, J=1.12 Hz, 1H) 7.43 (d, J=8.15 Hz, 1H) 7.71 (d, J=8.44 Hz,1H) 7.91 (d, J=2.20 Hz, 1H). LCMS (MH+): 613.

Example 3a:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(320 mg, 0.413 mmol) in CH₂Cl₂ (5.0 mL) was added methanesulfonylchloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), andthe reaction was stirred for 1.5 h at RT and then concentrated in vacuo.The product was purified by column chromatography using an Isco Goldreversed phase silica cartridge (100% CH₂Cl₂ to 90:9:1 CH₂Cl₂:MeOH:conc.NH₄OH) to provide (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 2:

A solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(290 mg, 0.340 mmol, Step 1) in MeOH (10 mL) was hydrogenated in anH-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and Theproduct was purified by column chromatography using an Isco Goldreversed phase silica cartridge (100% CH₂Cl₂ to 90:9:1 CH₂Cl₂:MeOH:conc.NH₄OH) to provide (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Step 3:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using theLiOH general method provided the title compound as an off-white solid.

1H NMR (400 MHz, MeOH-d4): δ ppm 1.53-1.65 (m, 4H) 1.80 (qd, J=12.57,3.98 Hz, 2H) 1.94-2.02 (m, 2H) 2.02-2.12 (m, 1H) 2.31 (dd, J=13.42, 9.27Hz, 1H) 2.38 (s, 3H) 2.67-2.94 (m, 3H) 2.86 (s, 3H) 3.07-3.28 (m, 2H)3.37-3.74 (m, 4H) 3.78-3.92 (m, 2H) 4.08 (dd, J=9.15, 7.20 Hz, 1H) 5.71(s, 1H) 6.39 (d, J=2.29 Hz, 1H) 6.64-6.82 (m, 1H) 7.31 (d, J=1.71 Hz,1H) 7.42 (dd, J=8.25, 1.76 Hz, 1H) 7.67 (d, J=8.10 Hz, 1H) 7.89 (d,J=2.29 Hz, 1H). LCMS (MH+): 693.

Using the generic scheme below, the following examples of Table 2a canbe prepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 3a).

TABLE 2a

Ex. LCMS No. Cy CAS Name (MH+) 3b

(S)-8-(6-((R)-1-(4-(1-acetylpiperidin-4-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 656.7 3c

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane-3-carboxylic acid 615.6

TABLE 2b NMR Data for Compounds of Table 2a Ex. No. 1H NMR 3b ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.54-1.82 (m, 6 H) 1.86-1.99 (m, 2 H)2.05-2.18 (m, 4 H) 2.36-2.38 (m, 3 H) 2.48 (dd, J = 13.69, 8.86 Hz, 1 H)2.66-2.81 (m, 1 H) 2.88-3.03 (m, 1 H) 3.19-3.27 (m, 1 H) 3.31-3.40 (m, 1H) 3.60-3.95 (m, 4 H) 4.05 (d, J = 13.08 Hz, 1 H) 4.55 (t, J = 8.66 Hz,1 H) 4.67 (d, J = 13.13 Hz, 1 H) 6.39 (d, J = 2.39 Hz, 1 H) 6.50 (br.s., 1 H) 6.79-6.87 (m, 1 H), 7.36 (s, 1 H) 7.47 (dd, J = 8.22, 1.64 Hz,1 H) 7.64 (d, J = 8.30 Hz, 1 H) 7.86 (d, J = 2.39 Hz, 1 H) 3c ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.59 (d, J = 5.08 Hz, 4 H) 1.72-1.89 (m, 4 H)2.06 (dd, J = 13.45, 7.15 Hz, 1 H) 2.32 (dd, J = 13.45, 9.25 Hz, 1 H)2.38 (s, 3 H) 2.82-2.95 (m, 1 H) 3.07-3.16 (m, 1 H) 3.25 (d, J = 11.76Hz, 1 H) 3.36-3.74 (m, 6 H) 4.03 (dt, J = 11.16, 2.96 Hz, 2 H) 4.08 (dd,J = 9.15, 7.20 Hz, 1 H) 5.71 (s, 1 H) 6.39 (d, J = 2.29 Hz, 1 H) 6.72(q, J = 6.75 Hz, 1 H) 7.29 (d, J = 1.71 Hz, 1 H) 7.41 (dd, J = 8.20,1.76 Hz, 1 H) 7.67 (d, J = 8.10 Hz, 1 H) 7.88 (d, J = 2.34 Hz, 1 H)

Example 4:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (product of Step 3, Example 10m) (135 mg, 0.18 mmol) in dioxane (2mL) was added (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid (84 mg,0.4 mmol) and Cs₂CO₃ (48 mg, 0.16 mmol). The reaction was heated to 80°C. for 16 h, cooled to RT, and filtered. The solvent was removed invacuo. Purification via normal phase silica gel chromatography(CH₂Cl₂/Heptane) provided(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as an off-white solid.

Step 2:

N-CBZ Deprotection was accomplished via method B to yield(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.66 (d, J=5.47 Hz, 4H) 2.03-2.17 (m,1H) 2.42 (s, 4H) 3.16-3.30 (m, 2H) 3.47-3.81 (m, 4H) 3.89 (s, 3H) 3.97(s, 3H) 4.26-4.45 (m, 1H) 6.40-6.52 (m, 1H) 6.82-6.96 (m, 1H) 7.30-7.37(m, 1H) 7.40 (s, 1H) 7.76 (s, 1H) 7.80-7.93 (m, 4H) 7.99-8.09 (m, 1H).LCMS: 696.7.

Example 5a:(S)-8-(2-amino-6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made according to the procedures described for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 4).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.42 (t, J=7.13 Hz, 3H) 1.61 (br. s.,4H) 2.02-2.14 (m, 1H) 2.28-2.40 (m, 1H) 2.42 (s, 3H) 3.06-3.19 (m, 1H)3.21-3.30 (m, 1H) 3.40-3.60 (m, 2H) 3.62-3.80 (m, 2H) 4.01-4.19 (m, 1H)4.41 (d, J=7.22 Hz, 2H) 5.76 (s, 1H) 6.45 (d, J=2.34 Hz, 1H) 6.79-6.92(m, 1H) 7.60 (s, 1H) 7.70 (d, J=1.56 Hz, 1H) 7.80 (d, J=1.56 Hz, 1H)7.84 (s, 1H) 7.90-7.97 (m, 1H) 8.02 (d, J=2.15 Hz, 1H) 8.05 (s, 1H) 8.31(s, 1H) 680.7. LCMS (MH+): 578.7.

Example 5b:(S)-8-(2-amino-6-((R)-1-(4′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made according to the procedures described for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 4).

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 4H), 1.30 (d, J=17.4 Hz, 10H),1.40 (t, J=7.1 Hz, 4H), 1.59 (d, J=5.8 Hz, 5H), 2.05 (dd, J=13.5, 7.2Hz, 1H), 2.35 (m, 5H), 3.11 (d, J=11.7 Hz, 1H), 3.24 (d, J=11.7 Hz, 1H),3.49 (ddd, J=28.1, 12.7, 5.7 Hz, 2H), 3.66 (dd, J=13.2, 7.3 Hz, 3H),4.07 (t, J=8.1 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 4.82 (d, J=9.7 Hz, 1H),4.91 (s, 2H), 5.75 (s, 1H), 6.42 (d, J=2.4 Hz, 1H), 6.83 (q, J=6.5 Hz,1H), 7.72 (d, J=1.6 Hz, 1H), 7.81 (m, 4H), 8.00 (d, J=2.4 Hz, 1H), 8.10(m, 2H). LCMS (MH+): 681.

Example 6:(S)-8-(2-amino-6-((R)-1-(4-(3-carboxypropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of 9-borabicyclo[3.3.1]nonane (2.0 mL, 0.5 M in THF, 1.0mmol) was added methyl but-3-enoate (100 μL, 1.0 mmol) and stirred at RTfor 2 h to prepare the 9-BBN/butane solution.

Step 2:

To a solution of(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (250 mg,0.32 mmol) in THF (2 mL) was added sequentially PdCl₂(dppf)CH₂Cl₂ (8 mg,0.01 mmol), NaOEt (66 mg, 1 mmol) and the prepared 9-BBN/butene solutionfrom Step 1. The reaction was heated to 65° C. for 2 h, then cooled toRT. The reaction was extracted with EtOAc, brine and dried over Na₂SO₄and concentrated in vacuo. The product was purified by columnchromatography using an Isco Gold reversed phase silica cartridge (100%CH₂Cl₂ to 90:9:1 CH₂Cl₂:MeOH:conc. NH₄OH) to provide (S)-2-benzyl3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as anoff-white solid.

Step 3:

N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as anoff-white solid.

Step 4:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylatewas carried out using the LiOH general method providing the titlecompound as an off-white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.40-1.61 (m, 4H) 1.76-1.93 (m, 3H)2.24 (t, J=7.35 Hz, 2H) 2.27-2.37 (m, 4H) 2.58-2.74 (m, 2H) 3.10 (br.s., 2H) 3.53 (br. s., 4H) 4.42 (br. s., 1H) 5.71 (br. s., 1H) 6.00 (br.s., 2H) 6.38 (d, J=2.20 Hz, 1H) 7.00 (q, J=6.87 Hz, 1H) 7.29 (d, J=1.51Hz, 1H) 7.32-7.41 (m, 1H) 7.60 (s, 1H) 8.05 (d, J=2.29 Hz, 1H) 8.94 (br.s., 1H) 10.20 (br. s, 1H) 12.14 (br. s., 1H). LCMS (MH+): 618.6.

Example 7:(S)-8-(2-amino-6-((R)-1-(4-(2-carboxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made as described for(S)-8-(2-amino-6-((R)-1-(4-(3-carboxypropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 6).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.56 (t, J=5.54 Hz, 4H) 1.97 (s, 2H)2.04 (dd, J=13.30, 7.10 Hz, 1H) 2.29 (dd, J=13.67, 9.18 Hz, 1H) 2.35 (s,3H) 2.59-2.68 (m, 2H) 2.97 (t, J=7.49 Hz, 2H) 3.06-3.13 (m, 1H) 3.23 (d,J=11.86 Hz, 1H) 3.39-3.55 (m, 2H) 3.57-3.75 (m, 2H) 4.06 (dd, J=9.05,7.30 Hz, 1H) 5.72 (s, 1H) 6.36 (d, J=2.29 Hz, 1H) 6.71 (q, J=6.61 Hz,1H) 7.28 (d, J=1.61 Hz, 1H) 7.37 (dd, J=8.20, 1.46 Hz, 1H) 7.62 (d,J=8.10 Hz, 1H) 7.83 (d, J=2.25 Hz, 1H). LCMS (MH+): 604.

Example 9:(S)-8-(2-amino-6-((R)-1-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (product of Step 3, Example 10m) (240 mg, 0.33 mmol) in ethanol (8mL) was added (E)-ethyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (110 mg, 0.49mmol), PdCl₂(PPh₃)₂ (20 mg, 0.049 mmol) and KHCO₃ (170 mg, 0.05 mmol).The reaction was heated to 80° C. for 2 h, cooled to RT, and filtered.The solvent was removed in vacuo. Purification via normal phase silicagel chromatography (CH₂Cl₂/heptane) provided((S)-8-(2-amino-6-((R)-1-(4-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((((2E,4Z)-2-vinylhexa-2,4-dien-1-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as a white solid.

Step 2:

To a solution of((S)-8-(2-amino-6-((R)-1-(4-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((((2E,4Z)-2-vinylhexa-2,4-dien-1-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (180 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cubeapparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0mL/min at RT. The resulting eluent was concentrated in vacuo and theproduct was purified by column chromatography using an Isco Goldreversed phase silica cartridge (100% CH₂Cl₂ to 90:9:1 CH₂Cl₂:MeOH:conc.NH₄OH) to provide the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.14 (t, J=7.15 Hz, 3H) 1.50-1.68 (m,4H) 1.94-1.99 (m, 2H) 2.04 (dd, J=13.45, 7.20 Hz, 1H) 2.30 (dd, J=13.47,9.27 Hz, 1H) 2.35 (s, 3H) 2.66 (t, J=7.54 Hz, 2H) 2.97 (t, J=7.52 Hz,2H) 3.07-3.14 (m, 1H) 3.23 (d, J=11.76 Hz, 1H) 3.39-3.72 (m, 4H)4.01-4.11 (m, 3H) 5.70 (s, 1H) 6.36 (d, J=2.34 Hz, 1H) 6.72 (q, J=6.72Hz, 1H) 7.27 (d, J=1.61 Hz, 1H) 7.35 (dd, J=8.15, 1.61 Hz, 1H) 7.62 (d,J=8.05 Hz, 1H) 7.83 (d, J=2.34 Hz, 1H). LCMS (MH+): 632.1

Example 10d:(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol(40 g, 138 mmol) in dioxane (400 mL) was added4,6-dichloropyrimidin-2-amine (113 g, 690 mmol) and Cs₂CO₃ (132 g, 405mmol). The mixture was heated for 24 h at 80° C. The reaction was thencooled to RT and filtered. The solvent was removed in vacuo, then CH₂Cl₂and heptane was added. The solvent volume was reduced until a solidprecipitated out. The solid was filtered and the procedure repeatedseveral times to provide4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amineas a white solid.

Step 2:

To a solution of4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-2-amine(57.3 g, 137 mmol, Step 1) in dioxane (500 mL) was added (S)-2-benzyl3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (48 g, 124.9 mmol),and NaHCO₃ (31.5 g, 375 mmol). After 5 h, an additional amount of NaHCO₃(31.5 g, 375 mmol) was added and the reaction mixture was heated to 90°C. for 36 h. The reaction was then cooled to RT and filtered.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylatean off-white solid.

Step 4:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as anoff-white solid.

Using the generic scheme below, the following examples of Table 3a wereprepared as described above for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d).

TABLE 3a

Ex. LCMS No. R′ R″ R′′′ CAS Name (MH+) 10a H H H8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H- 532pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10b H Cl H8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H- 566pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10c H Cl H(R)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H- 566pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid R-Spiro 10d H Cl H(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H- 566pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10e H H H(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl- 5321H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10f H H Cl(S)-8-(2-amino-6-((R)-1-(3-chloro-2-(3-methyl-1H- 566.9pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10g H CF₃ H(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl- 600.61H-pyrazol-1-yl)-4- (trifluoromethyl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10h H CH₃ H(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methyl-2- 546.6(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10i H F H8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-fluoro-2-(3- 550.5methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10j H

H 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methoxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 564.6 10k Cl H H8-(2-amino-6-((R)-1-(5-chloro-2-(3-methyl-1H- 566.9pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10l H

H (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-methoxy-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- 564.6diazaspiro[4.5]decane-3-carboxylic acid 10m H Br H(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H- 611pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 10n Br H H(S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H- 611.5pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid * Stereochemistry defined inname in table below

TABLE 3b NMR Data for Compounds of Table 3a Ex. No. NMR 10a ¹H NMR (400MHz, MeOH-d4): δ ppm 1.59 (br. s., 4 H) 1.97-2.12 (m, 1 H) 2.24-2.35 (m,1 H) 2.39 (s, 3 H) 3.11 (s, 1 H) 3.22 (s, 1 H) 3.40-3.58 (m, 2 H) 3.66(br. s., 2 H) 3.95-4.17 (m, 1 H), 5.73 (s, 1 H) 6.39 (s, 1 H) 6.70-6.88(m, 1 H) 7.42 (d, J = 7.52 Hz, 1 H) 7.53 (dd, J = 12.93, 7.57 Hz, 2 H)7.75 (d, J = 7.52 Hz, 1 H) 7.87 (s, 1 H) 10b ¹H NMR (400 MHz, MeOH-d4) δppm 1.44-1.74 (m, 4 H) 1.88-2.06 (m, 1 H) 2.17-2.31 (m, 1 H) 2.39 (s, 3H) 2.86-3.04 (m, 1 H) 3.09 3.21 (m, 1 H) 3.41-3.57 (m, 2 H) 3.58-3.77(m, 2H) 3.85-4.05 (m, 1H) 5.63-5.76 (m, 1 H) 6.36-6.48 (m, 1 H) 6.766.91 (m, 1 H) 7.46-7.60 (m, 2 H) 7.67-7.79 (m, 1 H) 7.90-8.03 (m, 1 H)10c ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (br. s., 4 H) 2.04-2.17 (m, 1H) 2.41 (s, 4 H) 3.10-3.21 (m, 1 H) 3.27 (s, 1 H) 3.44-3.58 (m, 2 H)3.60-3.79 (m, 2 H) 4.05-4.18 (m, 1 H) 5.71 (s, 1 H) 6.44 (d, J = 2.15Hz, 1 H) 6.75-6.91 (m, 1 H) 7.52 (s, 2 H) 7.66-7.80 (m, 1 H) 7.96 (d, J= 2.15 Hz, 1 H) 10d ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (t, J = 5.30Hz, 4 H) 1.97-2.12 (m, 1 H) 2.31 (dd, J = 13.45, 9.25 Hz, 1 H) 2.38 (s,3 H) 3.11 (d, J = 11.76 Hz, 1 H) 3.25 (d, J = 11.71 Hz, 1 H) 3.38-3.57(m, 2 H), 3.58-3.74 (m, 2 H) 4.08 (dd, J = 9.15, 7.15 Hz, 1 H) 5.69 (s,1 H) 6.41 (d, J = 2.39 Hz, 1 H) 6.82 (q, J = 6.61 Hz, 1 H) 7.44-7.57 (m,2 H) 7.71 (d, J = 8.35 Hz, 1 H) 7.93 (d, J = 2.34 Hz, 1 H) 10e ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.71 (dt, J = 18.13, 5.48 Hz, 4 H) 2.08 (dd, J= 13.62, 8.49 Hz, 1 H) 2.37 (s, 3 H) 2.47 (dd, J = 13.59, 8.96 Hz, 1 H)3.62-3.90 (m, 4 H) 4.54 (t, J = 8.71 Hz, 1 H) 6.38 (d, J = 2.34 Hz, 1 H)6.48 (br. s., 1 H) 6.85 (q, J = 6.04 Hz, 1 H) 7.46 (dd, J = 7.86, 1.07Hz, 1 H) 7.52-7.59 (m, 1 H) 7.61-7.67 (m, 1 H) 7.70 (d, J = 7.76 Hz, 1H) 7.84 (d, J = 2.39 Hz, 1 H) 10f ¹H NMR (400 MHz, MeOH-d4): δ ppm1.49-1.68 (m, 4 H) 2.04 (dd, J = 13.45, 7.15 Hz, 1 H) 2.30 (dd, J =13.45, 9.25 Hz, 1 H) 2.35 (s, 3 H) 3.05-3.26 (m, 2 H) 3.38-3.77 (m, 5 H)4.06 (dd, J = 9.10, 7.15 Hz, 1 H) 5.60 (s, 1 H) 6.18 (q, J = 6.56 Hz, 1H) 6.39 (d, J = 2.34 Hz, 1 H) 7.49-7.59 (m, 1 H) 7.60-7.74 (m, 3 H) 10g¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51-1.64 (m, 4 H) 2.03 (dd, J = 13.45,7.15 Hz, 1 H) 2.29 (dd, J = 13.47, 9.27 Hz, 1 H) 2.37 (s, 3 H) 3.03-3.25(m, 2 H) 3.37-3.54 (m, 2 H) 3.56-3.75 (m, 2 H), 4.04 (dd, J = 9.08, 7.22Hz, 1 H) 5.66 (s, 1 H) 6.42 (d, J = 2.34 Hz, 1 H) 6.90 (q, J = 6.54 Hz,1 H) 7.73 (s, 1 H) 7.78 (d, J = 8.25 Hz, 1 H) 7.91 (d, J = 8.35 Hz, 1 H)7.98 (d, J = 2.34 Hz, 1 H) 10h ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (t,J = 5.25 Hz, 4 H) 2.05 (dd, J = 13.45, 7.15 Hz, 1 H) 2.30 (dd, J = 1.00Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H) 3.05-3.17 (m, 1 H) 3.21-3.29 (m, 1H) 3.36-3.75 (m, 4 H) 4.09 (dd, J = 9.10, 7.25 Hz, 1 H) 5.73 (s, 1 H)6.37 (d, J = 2.25 Hz, 1 H) 6.71 (d, J = 6.69 Hz, 1 H) 7.23 (d, J = 0.68Hz, 1 H) 7.31 (d, J = 8.10 Hz, 1 H) 7.60 (d, J = 8.05 Hz, 1 H) 7.84 (d,J = 2.29 Hz, 1 H) 10i ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.52-1.91 (m, 4H) 2.05-2.16 (m, 1 H) 2.40 (s, 3 H) 2.45-2.69 (m, 1 H) 3.52-4.13 (m, 4H) 4.57 (d, J = 17.28 Hz, 1 H) 6.43 (d, J = 2.25 Hz, 1 H) 6.88-7.09 (m,1 H) 7.23-7.51 (m, 2 H) 7.68-7.83 (m, 1 H) 7.92 (d, J = 2.29 Hz, 1H) 10j¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J = 4.54 Hz, 4 H) 2.00-2.12(m, 1 H) 2.27-2.35 (m, 1 H) 2.38 (s, 3 H) 3.05-3.17 (m, 1 H) 3.25 (d, J= 11.71 Hz, 1 H) 3.48 (dd, J = 1.17, 0.20 Hz, 2 H) 3.66 (d, J = 5.52 Hz,2 H) 3.85 (s, 3 H) 4.08 (dd, J = 9.08, 7.27 Hz, 1 H) 5.72 (s, 1 H) 6.38(d, J = 2.29 Hz, 1 H) 6.67 (d, J = 6.69 Hz, 1 H) 6.94 (d, J = 2.64 Hz, 1H) 7.06 (dd, J = 8.83, 2.59 Hz, 1 H) 7.63 (d, J = 8.83 Hz, 1 H) 7.87 (d,J = 2.29 Hz, 1 H) 10k ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.18-1.36(m, 3 H) 1.43 (t, J = 6.74 Hz, 3 H) 1.54-2.29 (m, 6 H) 2.39 (br.s., 3 H)3.78 (br. s., 4 H) 4.26 (br. s., 2 H) 4.42 (d, J = 6.15 Hz, 2 H) 5.53(br. s., 1 H), 6.36 (s, 1 H) 6.59 (br. s., 1 H) 7.48 (d, J = 7.96 Hz, 1H), 7.61 (br. s. 1 H) 8.16 (d, J = 8.05 Hz, 1 H) 8.34 (br. s., 1 H) 10l¹H NMR (400 MHz, DICHLOROMETHANE-d2): δ ppm 1.40-1.61 (m, 4 H) 1.95 (dd,J = 12.89, 5.86 Hz, 1 H) 2.14-2.28 (m, 1 H) 2.36 (s, 3 H) 3.07 (d, J =1.00 Hz, 1 H) 3.16 (d, J = 1.00 Hz, 1 H) 3.36 (br. s., 2 H), 3.54 (br.s., 2 H) 3.79 (s, 3 H) 4.08 (t, J = 7.71 Hz, 1 H) 4.71-5.04 (m, 2 H)5.47 (s, 1 H) 6.30 (d, J = 2.10 Hz, 1 H) 6.65 (q, J = 7.11 Hz, 1 H) 6.87(d, J = 2.64 Hz, 1 H) 6.95 (dd, J = 8.86, 2.61 Hz, 1 H), 7.61 (d, J =8.74 Hz, 1 H) 7.65 (d, J = 2.20 Hz, 1 H) 10m ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.64 (d, J = 4.69 Hz, 4 H) 2.03-2.15 (m, 1 H) 2.40 (s, 4 H)3.12-3.31 (m, 2 H) 3.43-3.63 (m, 2 H) 3.64-3.78 (m, 2 H) 4.16-4.34 (m, 1H) 6.43 (d, J = 2.34 Hz,, 1 H) 6.76-6.91 (m, 1 H) 7.67 (dd, J = 5.76,4.20 Hz, 3 H) 7.94 (d, J = 2.15 Hz, 1 H) 10n ¹H NMR (400 MHz, DMSO-d6):δ ppm 1.47-1.71 (m, 4 H) 1.90 (dd, J = 13.15, 9.15 Hz, 1 H) 2.24-2.39(m, 4 H) 3.13 (t, J = 5.25 Hz, 2 H) 3.66 (br. s., 4 H) 4.39-4.51 (m, 2H) 6.05 (s, 1 H) 6.42 (d, J = 2.34 Hz, 1 H) 7.25 (d, J = 5.27 Hz, 1 H)7.51 (d, J = 8.59 Hz, 1 H) 7.78 (s, 1 H) 7.85 (dd, J = 8.54, 2.29 Hz, 1H) 8.11 (d, J = 2.34 Hz, 1 H) 8.95 (d, J = 6.69 Hz, 1 H) 10.20 (br. s.,1 H)

Example 10o:(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d) starting with(R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol(Intermediate 38).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J=7.7 Hz, 2H), 1.61 (q, J=6.5,5.3 Hz, 4H), 2.06 (dd, J=13.5, 7.4 Hz, 1H), 2.36 (dd, J=13.5, 9.1 Hz,1H), 3.15 (d, J=11.9 Hz, 1H), 3.26 (d, J=11.7 Hz, 1H), 3.47 (ddt,J=21.7, 13.4, 5.8 Hz, 2H), 3.63 (m, 2H), 4.18 (t, J=8.2 Hz, 1H), 6.63(q, J=6.8 Hz, 1H), 7.50 (m, 7H). LCMS (MH+): 607.

Example 10p:(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with(R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(Intermediate 39).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.53 (d, J=5.08 Hz, 4H) 1.77-1.87 (m,1H) 2.03-2.20 (m, 1H) 2.75 (s, 1H) 2.99 (s, 1H) 3.37-3.53 (m, 2H)3.54-3.66 (m, 2H) 3.66-3.77 (m, 1H) 5.56 (s, 1H) 6.53-6.70 (m, 1H) 6.96(d, J=2.34 Hz, 1H) 7.62 (dd, J=4.30, 2.34 Hz, 2H), 7.76 (s, 1H) 8.25 (d,J=1.37 Hz, 1H). LCMS (MH+): 620.

Example 10pa:(S)-8-(2-amino-6-((R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with(R)-1-(2-(3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanol(Intermediate 40).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.40 (s, 9H) 1.51-1.68 (m, 4H)1.99-2.12 (m, 1H) 2.25-2.41 (m, 1H) 3.05-3.16 (m, 1H) 3.20-3.28 (m, 1H)3.38-3.55 (m, 2H) 3.56-3.73 (m, 2H) 4.00-4.16 (m, 1H) 5.57 (s, 1H) 6.52(d, J=2.34 Hz, 1H) 7.15-7.28 (m, 1H) 7.44-7.53 (m, 1H) 7.56 (d, J=1.95Hz, 1H) 7.68-7.79 (m, 1H) 7.95 (d, J=2.34 Hz, 1H). LCMS (MH+): 609.

Example 10q:(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with(R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(Intermediate 41).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.36 (dd, J=6.93, 1.07 Hz, 6H) 1.57(br. s., 4H) 1.86-2.03 (m, 1H) 2.15-2.30 (m, 1H) 2.86-3.00 (m, 1H)3.02-3.19 (m, 2H) 3.39-3.55 (m, 2H) 3.57-3.73 (m, 2H) 3.82-3.98 (m, 1H)5.63 (s, 1H) 6.40-6.56 (m, 1H) 6.93-7.10 (m, 1H) 7.54 (s, 2H) 7.67-7.78(m, 1H) 7.91-8.02 (m, 1H). LCMS (MH+): 595.

Example 10r:(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with(R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(Intermediate 42).

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.77-0.90 (m, 2H) 0.95-1.08 (m, 2H)1.49-1.65 (m, 4H) 1.80-1.95 (m, 1H) 1.99-2.10 (m, 1H) 2.10-2.24 (m, 1H)2.74-2.85 (m, 1H) 3.00-3.11 (m, 1H) 3.38-3.69 (m, 4H) 3.72-3.84 (m, 1H)5.56-5.70 (m, 1H) 6.29-6.38 (m, 1H) 6.89-7.05 (m, 1H) 7.52 (s, 2H)7.67-7.77 (m, 1H) 7.86-7.98 (m, 1H). LCMS (MH+): 593.

Example 11:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d) starting with(S)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanol(Intermediate 20)

Example 12a:(S)-8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(300 mg, 0.388 mmol, see Example 1u) in EtOH:H₂O (15 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (90 mg, 0.58 mmol),KHCO₃ (389 mg, 3.88 mmol), and PdCl₂(PPh₃)₂ (41 mg, 0.058 mmol). Thereaction mixture was heated to 80° C. for 1 h, then cooled to RT. Thereaction was diluted with water, extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification with a 40 g Isco RediSep silicacartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

N-CBZ Deprotection was accomplished via method A, which also reduced theolefin, to provide (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

Hydrolysis of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateusing the LiOH general method provided the title compound as a whitesolid.

Using the same scheme below, the following examples of Table 4a wereprepared as described above for(S)-8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 12a).

TABLE 4a

Ex. LCMS No. R CAS Name (MH+) 12a

(S)-8-(2-amino-6-((R)-1-(4-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 560 12b

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-propylphenyl)ethoxy)pyrimidin-4-yl)-2,8- 575diazaspiro[4.5]decane-3-carboxylic acid 12c

(S)-8-(2-amino-6-((R)-1-(4-butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- 588yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

TABLE 4b NMR Data for Compounds of Table 4a Ex. No. NMR 12a ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.59 Hz, 3 H), 1.50-1.69 (m, 4 H),2.01-2.35 (m, 2 H), 2.37 (s, 3 H), 2.72 (q, J = 7.57 Hz, 2 H), 3.05-3.28(m, 2 H), 3.40-3.76 (m, 4 H), 4.08 (dd, J = 8.88, 7.32 Hz, 1 H), 5.72(s, 1 H), 6.38 (d, J = 2.25 Hz, 1 H), 6.71 (q, J = 6.70 Hz, 1 H), 7.25(d, J = 1.56 Hz, 1 H), 7.35 (dd, J = 8.18, 1.59 Hz, 1 H), 7.63 (d, J =8.15 Hz, 1 H), 7.85 (d, J = 2.29 Hz, 1 H) 12b ¹H NMR (400 MHz, MeOH-d4):δ ppm 0.96 (t, J = 7.35 Hz, 3 H), 1.49-1.62 (m, 4 H), 1.62-1.77 (m, 2H), 2.01-2.35 (m, 2 H), 2.37 (s, 3 H), 2.59-2.74 (m, 2 H), 3.06-3.29 (m,2 H), 3.39-3.77 (m, 4 H), 4.08 (dd, J = 9.05, 7.30 Hz, 1 H), 5.72 (s, 1H), 6.37 (d, J = 2.29 Hz, 1 H), 6.71 (q, J = 6.72 Hz, 1 H), 7.23 (d, J =1.56 Hz, 1 H), 7.33 (dd, J = 8.15, 1.56 Hz, 1 H), 7.63 (d, J = 8.05 Hz,1 H), 7.85 (d, J = 2.29 Hz, 1 H) 12c ¹H NMR (400 MHz, MeOH-d4): δ ppm0.94 (t, J = 7.35 Hz, 3 H), 1.38 (dq, J = 14.92, 7.39 Hz, 2 H),1.49-1.72 (m, 6 H), 2.01-2.35 (m, 2 H), 2.37 (s, 3 H), 2.60-2.74 (m, 2H), 3.07-3.28 (m, 2 H), 3.40-3.74 (m, 4 H), 4.08 (dd, J = 9.15, 7.20 Hz,1 H), 5.71 (s, 1 H), 6.38 (d, J = 2.15 Hz, 1 H), 6.63-6.77 (m, 1 H),7.23 (d, J = 1.61 Hz, 1 H), 7.33 (dd, J = 8.10, 1.66 Hz, 1 H), 7.63 (d,J = 8.05 Hz, 1 H), 7.85 (d, J = 2.29 Hz, 1 H)

Example 13:(3S)-8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(product of Step 1, Example 12b)(373 mg, 0.518 mmol) in 4:1 acetone:H₂O(20 mL) was added OsO₄ (313 μL, of a 4% (w/w) aqueous solution, 325 mg,0.0518 mmol) and N-methylmorpholine-N-oxide (214 μL of a 50% (w/w)aqueous solution, 242 mg, 1.04 mmol). The reaction was stirred at RT for24 h, concentrated in vacuo, and the residue was purified bychromatography on a 50 g Isco Gold RediSep reversed phase silicacartridge (H₂O:HOAc: 99:1 to EtOH:HOAc 99:1). A second purification on a40 g Isco RediSep silica cartridge eluting (CH₂Cl₂ 100% to 90:9:1CH₂Cl₂:EtOH:NH₄OH) provided (3S)-2-benzyl 3-ethyl8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

N-CBZ deprotection was accomplished via method A to provide (3S)-ethyl8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of (3S)-ethyl8-(2-amino-6-((1R)-1-(4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provides the title compound as a whitesolid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.49-1.66 (m, 4H) 2.05 (dd, J=13.50,7.20 Hz, 1H) 2.31 (dd, J=13.45, 9.20 Hz, 1H) 2.38 (s, 3H) 3.04-3.28 (m,2H) 3.38-3.76 (m, 6H) 4.08 (dd, J=8.98, 7.27 Hz, 1H) 4.67-4.79 (m, 1H)5.72 (d, J=2.15 Hz, 1H) 6.39 (d, J=2.29 Hz, 1H) 6.77 (q, J=6.65 Hz, 1H)7.45 (s, 1H) 7.52 (d, J=8.20 Hz, 1H) 7.71 (d, J=8.15 Hz, 1H) 7.88 (dd,J=4.20, 2.34 Hz, 1H). LCMS (MH+): 592.

Example 14:(S)-8-(2-amino-6-((R)-1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (3S)-2-benzyl 3-ethyl8-(2-amino-6-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(730 mg, 1.0 mmol), was added ZnCN₂ (280 mg, 2.4 mmol), Zn (64 mg, 1.0mmol), DMA (10 mL), and Pd(P-t-Bu₃)₂ (78 mg, 0.15 mmol). The reactionmixture was heated in a sealed vial at 115° C. for 2 h, then cooled toRT, filtered, and concentrated in vacuo. Purification by normal phasesilica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a viscousoil.

Step 2:

N-CBZ Deprotection was accomplished via Method A to provide (3S)-ethyl8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas an off-white solid.

Step 3:

Hydrolysis of (3 S)-ethyl8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provides the title compound as anoff-white solid.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.47-1.71 (m, 4H) 1.95-2.10 (m, 1H)2.20-2.33 (m, 1H) 2.36 (s, 3H) 2.96-3.24 (m, 2H) 3.35-3.54 (m, 2H)3.55-3.79 (m, 2H) 3.92-4.13 (m, 1H) 5.65 (s, 1H) 6.42 (d, J=2.15 Hz, 1H)6.95 (q, J=6.72 Hz, 1H) 7.70-7.91 (m, 3H) 7.97 (d, J=2.25 Hz, 1H). LCMS(MH+): 556.

Example 15:(S)-8-(2-amino-6-((R)-1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (3S)-2-benzyl 3-ethyl8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(150 mg, 0.2 mmol, see Ex. 14) in toluene (10 mL) was added acetaldehydeoxime (240 mg, 4 mmol) and InCl₃ (44 mg, 0.2 mmol). The reaction washeated to 110° C. for 3 h, then cooled to RT, and concentrated in vacuo.Purification by normal phase silica gel column (EtOAc/hepate) provided(3 S)-2-benzyl 3-ethyl8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

N-CBZ Deprotection was accomplished via Method A to provide (3S)-ethyl8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of (3 S)-ethyl8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provides the title compound as a whitesolid.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.56 (t, J=4.98 Hz, 5H) 2.03 (dd,J=13.47, 7.03 Hz, 1H) 2.23-2.33 (m, 2H) 2.35-2.39 (m, 3H) 3.04-3.12 (m,1H) 3.22 (d, J=11.71 Hz, 1H) 3.37-3.72 (m, 5H) 4.05 (dd, J=9.20, 7.05Hz, 1H) 5.70 (s, 1H) 6.40 (d, J=2.39 Hz, 1H) 6.82-6.92 (m, 1H) 7.80 (d,J=8.10 Hz, 1H) 7.87-7.97 (m, 4H). LCMS (MH+): 575.

Example 16:(S)-8-(2-amino-6-((R)-1-(4-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

Step 1:

To a solution of (3S)-2-benzyl 3-ethyl8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(0.35 g, 0.50 mmol, see Ex. 14) in MeOH (5 mL) and water (1 mL) wasadded LiOH—H₂O (0.20 g, 5 mmol). The mixture was heated to 50° C.overnight. The reaction was then cooled to RT, and the reaction wasacidified with 6N HCl to pH=1. Concentration in vacuo followed byreverse phase HPLC purification (MeOH/water/HOAc) provided(3S)-8-(2-amino-6-(1-(4-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as a white solid.

Step 2:

N-CBZ Deprotection was accomplished via Method A to provide the titlecompound as a white solid.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.57 (t, J=5.42 Hz, 4H) 2.03 (dd,J=13.42, 7.42 Hz, 1H) 2.25-2.35 (m, 2H) 2.37 (s, 2H) 3.04-3.13 (m, 1H)3.16-3.25 (m, 1H) 3.38-3.75 (m, 5H) 4.06 (dd, J=9.03, 7.32 Hz, 1H) 5.72(s, 1H) 6.39 (d, J=2.29 Hz, 1H) 6.78-6.89 (m, 1H) 7.76 (d, J=8.15 Hz,1H) 7.90 (d, J=2.34 Hz, 1H) 7.95 (d, J=1.42 Hz, 1H) 8.04 (dd, J=8.13,1.59 Hz, 1H). LCMS (MH+): 576.

Example 17:(S)-8-(2-amino-6-((R)-1-(4-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(1.50 g, 1.94 mmol, See Ex. 1u) in THF (20 mL), MeOH (10 mL) and water(10 mL) was added LiOH—H₂O (0.80 g, 19.4 mmol), and the reaction wasstirred at RT for 4 h. The pH of the reaction mixture was adjusted to6.5 with 6 N HCl, and the organic solvents were removed in vacuo toprovide a white solid that is filtered away. The reaction mixture wasthen partitioned between water and EtOAc, and extracted. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, thenconcentrated in vacuo to provide(2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylicacid as a white solid that is used directly without furtherpurification.

Step 2:

To a solution of(2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylicacid (74 mg, 0.10 mmol, Step 2) in EtOH (4 mL) was added KHCO₃ (84 mg,1.0 mmol). The reaction mixture was degassed, fitted with a 1 atm COballoon, then treated with PdCl₂(PPh₃)₂ (14 mg, 0.02 mmol). The reactionwas degassed once more with 1 atm CO and then heated to 80° C. for 12 h.The reaction was cooled to RT, concentrated in vacuo and the residue waspartitioned between water and EtOAc, and extracted. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by normal phase silica gel column(CH₂Cl₂/AcOH/EtOH) provided(2S)-8-[2-amino-6-[(1R)-1-[4-ethoxycarbonyl-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylicacid as a white solid.

Step 3:

N-CBZ Deprotection was accomplished via Method A to provide the titlecompound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.37 (t, J=7.13 Hz, 3H) 1.58 (d, J=4.30Hz, 4H) 1.97 (s, 2H) 2.04 (dd, J=13.47, 7.27 Hz, 1H) 2.30 (dd, J=13.59,9.25 Hz, 1H) 2.38 (s, 3H) 3.05-3.27 (m, 2H) 3.39-3.76 (m, 4H) 3.99-4.10(m, 1H) 4.37 (q, J=7.13 Hz, 2H) 5.68 (s, 1H) 6.41 (d, J=2.34 Hz, 1H)6.84 (q, J=6.67 Hz, 1H) 7.83 (d, J=8.10 Hz, 1H) 7.94 (d, J=2.34 Hz, 1H)7.99 (d, J=1.61 Hz, 1H) 8.09 (dd, J=8.27, 1.68 Hz, 1H). LCMS (MH+): 604.

Example 18a:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (product of Step 3, Example 10m) (1.2 g, 1.6 mmol) in DMF (16 mL)was added benzyl bromide (0.27 g, 1.6 mmol) and NaHCO₃ (0.67 g, 8.0mmol). The reaction was then heated to 60° C. for 2 h, cooled to RT, andstirred for 12 h. The precipitate was filtered, washed with EtOAc andthe filtrate concentrated in vacuo. The residue was partitioned betweenwater and EtOAc, and extracted. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-dibenzyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas the white solid.

Step 2:

To a solution of (S)-dibenzyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylatefrom Step 1 (415 mg, 0.50 mmol) in 1,4-dioxane (8 mL) and water (4 mL)was added KHCO₃ (420 mg, 5.0 mmol), and the reaction was degassed with 1atm CO. Then PdCl₂(PPh₃)₂ (140 mg, 0.10 mmol) was added and the reactionmixture was treated with 1 atm CO (balloon). The reaction mixture washeated to 80° C. for 12 h, then cooled to RT, and concentrated in vacuo.The residue was partitioned between water and EtOAc, and extracted. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by normal phase silicagel column (CH₂Cl₂/MeOH/NH₄OH) provided4-[(1R)-1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoro-ethyl]-3-(3-methylpyrazol-1-yl)benzoicacid as a white solid.

Step 3:

To a solution of4-[(1R)-1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoro-ethyl]-3-(3-methylpyrazol-1-yl)benzoicacid (80 mg, 0.1 mmol) in CH₂Cl₂ (4 mL) was added DMAP (73 mg, 0.6mmol), (CF₃)₂MeCOH (108 mg, 0.6 mmol), followed by EDCI (114 mg, 0.6mmol). The reaction mixture was stirred at RT for 12 h, diluted withCH₂Cl₂ and washed with water. The aqueous solution was extracted withCH₂Cl₂. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column (EtOAc/heptane) provided dibenzyl(2S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[2-(3-methylpyrazol-1-yl)-4-[2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethoxy]carbonyl-phenyl]ethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2,3-dicarboxylate as awhite solid.

Step 4:

N-CBZ Deprotection was accomplished via Method A to provide the titlecompound as a white solid.

Using the generic scheme below, the following examples of Table 5a wereprepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 18a).

TABLE 5a

Ex. No. R CAS Name LCMS (MH+) 18a

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 740 18b

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4- (propoxycarbonyl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 618 18c

(S)-8-(2-amino-6-((R)-1-(4-(butoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 632 18d

(S)-8-(2-amino-6-((R)-1-(4-(tert-butoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 632 18e

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isobutoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 632 18f

(S)-8-(2-amino-6-((R)-1-(4-((cyclopentyloxy)carbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 644

TABLE 5b NMR Data for Compounds of Table 5a Ex. No. NMR 18a ¹H NMR (400MHz, MeOH-d4): δ ppm 1.58 (br. s., 4 H) 1.97 (s, 1 H) 2.04 (dd, J =13.50, 7.20 Hz, 1 H) 2.12 (s, 3 H) 2.31 (dd, J = 13.45, 9.30 Hz, 1 H)2.38 (s, 3 H) 3.04-3.27 (m, 2 H) 3.38-3.55 (m, 2 H) 3.64 (dd, J = 13.23,5.56 Hz, 2 H) 4.07 (t, J = 8.08 Hz, 1 H) 5.67 (s, 1 H) 6.43 (d, J = 2.34Hz, 1 H) 6.85 (q, J = 6.69 Hz, 1 H) 7.90 (d, J = 8.20 Hz, 1 H) 7.96 (dd,J = 8.20, 2.00 Hz, 2 H) 8.06 (dd, J = 8.27, 1.73 Hz, 1 H) 18b ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.01 (t, J = 7.44 Hz, 3 H) 1.58 (d, J = 4.49Hz, 4 H) 1.72-1.85 (m, 2 H) 1.97 (s, 1 H) 2.04 (dd, J = 13.35, 7.25 Hz,1 H) 2.30 (dd, J = 13.52, 9.13 Hz, 1 H) 2.38 (s, 3 H), 3.06-3.26 (m, 2H) 3.38-3.72 (m, 4 H) 4.00-4.12 (m, 1 H) 4.29 (t, J = 6.64 Hz, 2 H) 5.68(s, 1 H) 6.42 (d, J = 2.44 Hz, 1 H) 6.84 (q, J = 6.57 Hz, 1 H) 7.84 (d,J = 8.20 Hz, 1 H) 7.95 (d, J = 2.34 Hz, 1H) 7.98 (d, J = 1.61 Hz, 1 H)8.09 (dd, J = 8.22, 1.64 Hz, 1 H) 18c ¹H NMR (400 MHz, MeOH-d4): δ ppm0.97 (t, J = 7.42 Hz, 3 H) 1.46 (dq, J = 15.01, 7.48 Hz, 2 H) 1.58 (d, J= 4.83 Hz, 4 H) 1.68-1.82 (m, 2 H) 1.97 (s, 1 H) 2.04 (dd, J = 13.52,7.03 Hz, 1 H) 2.30 (dd, J = 13.42, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.07-3.25(m, 2 H) 3.38-3.71 (m, 4 H) 4.06 (dd, J = 9.15, 7.00 Hz, 1 H) 4.33 (t, J= 6.61 Hz, 2 H) 5.68 (s, 1 H) 6.42 (d, J = 2.39 Hz, 1 H) 6.84 (q, J =6.44 Hz, 1 H) 7.84 (d, J = 8.30 Hz, 1 H) 7.95 (d, J = 2.29 Hz, 1 H) 7.98(d, J = 1.61 Hz, 1 H) 8.08 (dd, J = 8.25, 1.71 Hz, 1 H) 18d ¹H NMR (400MHz, MeOH-d4): δ ppm 1.57 (s, 13 H) 1.97 (s, 2 H) 2.04 (dd, J = 13.50,7.15 Hz, 1 H) 2.30 (dd, J = 14.06, 9.96 Hz, 1 H) 2.38 (s, 3 H) 3.08-3.26(m, 2 H) 3.38-3.74 (m, 4 H) 4.01-4.14 (m, 1 H) 5.68 (s, 1 H) 6.41 (d, J= 2.34 Hz, 1 H) 6.80 (q, J = 6.64 Hz, 1 H) 7.80 (d, J = 8.15 Hz, 1 H)7.92 (dd, J = 7.88, 1.93 Hz, 2 H) 8.02 (dd, J = 8.27, 1.59 Hz, 1 H) 18e¹H NMR (400 MHz, MeOH-d4): δ ppm 1.00 (d, J = 6.74 Hz, 6 H) 1.52-1.64(m, 4 H) 1.97 (s, 2 H) 2.00-2.12 (m, 2 H) 2.30 (dd, J = 13.45, 9.35 Hz,1 H) 2.38 (s, 3 H) 3.07-3.26 (m, 2 H) 3.37-3.55 (m, 2 H) 3.58-3.70 (m, 2H) 4.06 (dd, J = 9.03, 7.17 Hz, 1 H) 4.12 (d, J = 6.59 Hz, 2 H) 5.68 (s,1 H) 6.42 (d, J = 2.39 Hz, 1 H) 6.84 (q, J = 6.51 Hz, 1 H) 7.84 (d, J =8.35 Hz, 1 H) 7.95 (d, J = 2.34 Hz, 1 H) 7.98 (d, J = 1.61 Hz, 1 H) 8.09(dd, J = 8.27, 1.68 Hz, 1 H) 18f ¹H NMR (400 MHz, MeOH-d4): δ ppm1.54-1.94 (m, 11 H) 1.97 (s, 3 H) 2.04 (dd, J = 13.35, 7.15 Hz, 1 H)2.24-2.35 (m, 1 H) 2.38 (s, 3 H) 3.02-3.27 (m, 2 H) 3.37-3.81 (m, 4 H)3.95-4.22 (m, 1H) 5.32-5.44 (m, 1 H) 5.67 (s, 1 H) 6.41 (d, J = 2.39 Hz,1 H) 6.82 (d, J = 6.39 Hz, 1 H) 7.82 (d, J = 8.30 Hz, 1 H) 7.94 (d, J =1.85 Hz, 2 H) 8.06 (dd, J = 8.15, 1.71 Hz, 1 H)

Example 19a:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(500 mg, 0.65 mmol) in 4:1 EtOH:H₂O (25 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (150 mg, 0.971 mmol),KHCO₃ (648 mg, 6.47 mmol), and PdCl₂(PPh₃)₂ (68 mg, 0.097 mmol). Thereaction mixture was heated to 80° C. for 1.75 h, then cooled to RT, andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification via a 40 g Isco RediSep silica cartridge eluting(EtOAc/hepate) provides (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 2:

N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas an off-white solid.

Step 3:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as a whitesolid.

Using the generic scheme below, the following examples of Table 6a wereprepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 19a).

TABLE 6a

Ex. LCMS No. R CAS Name (MH+) 19a

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 558.6 19b

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-((E)-prop-1-en-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 572.6 19c

(S)-8-(2-amino-6-((R)-1-(5-((E)-but-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 585.5 19d

(S)-8-(2-amino-6-((R)-1-(5-((E)-2-carboxyvinyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 602.6

TABLE 6b NMR Data for Compounds of Table 6a Ex. No. NMR 19a ¹H NMR (400MHz, MeOH-d4): δ ppm 1.59 (m, 4 H) 2.06 (dd, J = 13.42, 7.17 Hz, 1 H)2.31 (dd, J = 13.42, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.18 (m, 2 H) 3.59 (m,4 H) 4.07 (dd, J = 9.20, 7.20 Hz, 1 H) 5.36 (d, J = 10.98 Hz, 1 H) 5.75(s, 1 H) 5.85 (d, J = 17.62 Hz, 1 H) 6.39 (d, J = 2.34 Hz, 1 H) 6.80 (m,2 H) 7.38 (d, J = 8.30 Hz, 1 H) 7.63 (dd, J = 8.25, 2.00 Hz, 1 H) 7.74(s, 1 H) 7.87 (d, J = 2.29 Hz, 1 H) 19b ¹H NMR (400 MHz, MeOH-d4): δ ppm1.59 (m, 3 H) 1.90 (dd, J = 6.32, 1.20 Hz, 3 H) 2.06 (dd, J = 13.47,7.13 Hz, 1 H) 2.31 (dd, J = 13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 3.18 (m,2 H) 3.57 (m, 4 H) 4.08 (dd, J = 9.18, 7.17 Hz, 1 H) 5.75 (s, 1 H) 6.39(m, 3 H) 6.75 (q, J = 6.67 Hz, 1 H) 7.32 (d, J = 8.25 Hz, 1 H) 7.52 (dd,J = 8.30, 2.00 Hz, 1 H) 7.65 (s, 1 H) 7.84 (d, J = 2.34 Hz, 1 H) 19c ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.11 (t, J = 7.47 Hz, 3 H) 1.59 (d, J =4.59 Hz, 4 H) 2.06 (dd, J = 13.37, 7.22 Hz, 1 H) 2.28 (m, 3 H) 2.37 (s,3 H) 3.18 (m, 2 H) 3.59 (m, 4 H) 4.07 (dd, J = 9.10, 7.20 Hz, 1 H) 5.76(s, 1 H) 6.40 (m, 3 H) 6.76 (m, 1 H) 7.33 (d, J = 8.25 Hz, 1 H) 7.54(dd, J = 8.30, 2.05 Hz, 1 H) 7.66 (s, 1 H) 7.84 (d, J = 2.29 Hz, 1 H)19d ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 5.44 Hz, 4 H) 1.97 (s,3 H) 2.04 (dd, J = 13.72, 7.27 Hz, 1 H) 2.30 (dd, J = 13.32, 9.18 Hz,1H) 2.37 (s, 3 H) 3.07-3.25 (m, 2 H) 3.40-3.55 (m, 2 H) 3.65 (dd, J =9.27, 4.73 Hz, 2 H) 4.07 (t, J = 7.98 Hz, 1 H) 5.75 (s, 1 H) 6.40 (d, J= 2.34 Hz, 1 H) 6.51 (d, J = 16.20 Hz, 1 H) 6.94 (q, J = 6.52 Hz, 1 H)7.46 (d, J = 8.30 Hz, 1 H) 7.66 (d, J = 15.86 Hz, 1 H) 7.78 (dd, J =8.32, 1.88 Hz, 1 H) 7.87 (s, 1 H) 7.92 (d, J = 2.34 Hz, 1 H)

Using the generic scheme below, the following examples of Table 7a canbe prepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 19a), by substituting the alkylidene borolane with aboronic acid or ester.

TABLE 7a

Ex. LCMS No. Cy CAS Name (MH+) 19e

(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 536.7 19f

(S)-8-(2-amino-6-((R)-1-(3′-carboxy-4-(3-methyl-1H-Pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 652 19g

(S)-8-(2-amino-6-((R)-1-(4′-carboxy-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 652 19h

(S)-8-(2-amino-6-((R)-1-(3′-((E)-2-carboxyvinyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 678 19i

(S)-8-(2-amino-6-((R)-1-(4′-((E)-2-carboxyvinyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 678 19j

(S)-8-(2-amino-6-((R)-1-(3′-(2-carboxyethyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 680 19k

(S)-8-(2-amino-6-((R)-1-(4′-(2-carboxyethyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 680 19l

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(hydroxymethyl)-3′-methyl-4-(3-methyl-1H-pyrazol-1-yl-[1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652 19m

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 652 19n

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 608 19o

(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 644 19p

(S)-8-(2-amino-6-((R)-1-(3′,4′-dichloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 677 19q

(S)-8-(2-amino-6-((R)-1-(4′-chloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylicacid 643 19r

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(hydroxymethyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 639

TABLE 7b NMR Data for Compounds of Table 7a Ex. No. NMR 19e ¹H NMR (400MHz, MeOH-d4): δ ppm 1.57 (m, 4 H) 2.04 (dd, J = 13.62, 6.98 Hz, 1 H)2.32 (d, J = 11.96 Hz, 6 H) 2.40 (s, 3 H) 3.16 (m, 2 H) 3.55 (m, 4 H)4.07 (dd, J = 9.18, 7.22 Hz, 1 H) 5.79 (s, 1 H) 6.40 (d, J = 2.29 Hz, 1H) 6.85 (m, 1 H) 7.21 (d, J = 7.76 Hz, 1 H) 7.31 (m, 1 H) 7.36 (s, 1 H)7.45 (d, J = 8.25 Hz, 1 H) 7.75 (dd, J = 8.27, 2.12 Hz, 1 H) 7.90 (d, J= 2.20 Hz, 2 H) 19f ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.53-1.67 (m, 4 H)2.05 (dd, J = 13.42, 7.17 Hz, 1 H) 2.30 (dd, J = 13.42, 9.22 Hz, 1 H)2.40 (s, 3 H) 3.06-3.27 (m, 2 H) 3.39-3.74 (m, 4 H) 4.08 (dd, J = 9.13,7.27 Hz, 1 H) 5.79 (s, 1 H) 6.42 (d, J = 2.29 Hz, 1 H) 6.92 (q, J = 6.62Hz, 1 H) 7.53 (d, J = 8.25 Hz, 1 H) 7.57 (t, J = 7.76 Hz, 1 H) 7.77-7.87(m, 2 H) 7.94 (d, J = 2.34 Hz, 1 H) 7.97 (d, J = 1.42 Hz, 1 H) 8.04 (dt,J = 7.79, 1.23 Hz, 1 H) 8.24 (t, J = 1.61 Hz, 1 H) 19g ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.47-1.67 (m, 4 H) 2.05 (dd, J = 13.45, 7.20 Hz, 1 H)2.31 (dd, J = 13.37, 9.27 Hz, 1 H) 2.40 (s, 3 H) 2.99-3.28 (m, 2H)3.39-3.78 (m, 4H) 4.08 (dd, J = 9.08, 7.27 Hz, 1 H) 5.79 (s, 1 H) 6.42(d, J = 2.29 Hz, 1 H) 6.86-7.01 (m, 1 H) 7.53 (d, J = 8.30 Hz, 1 H)7.64-7.77 (m, 2 H) 7.85 (dd, J = 8.30, 2.15 Hz, 1 H) 7.94 (d, J = 2.34Hz, 1 H) 7.99 (d, J = 1.32 Hz, 1 H) 8.08-8.18 (m, 2 H) 19h ¹H NMR (400MHz, MeOH-d4): δ ppm 1.59 (t, J = 5.54 Hz, 4 H) 2.04 (dd, J = 13.45,7.39 Hz, 1 H) 2.32 (dd, J = 13.50, 9.25 Hz, 1 H) 2.41 (s, 3 H) 3.07-3.26(m, 2 H) 3.41-3.76 (m, 4 H) 4.08 (dd, J = 9.01, 7.30 Hz, 1 H) 5.81 (s, 1H) 6.42 (d, J = 2.29 Hz, 1 H) 6.57 (d, J = 16.01 Hz, 1 H) 6.86-6.97 (m,1 H) 7.48-7.57 (m, 2 H) 7.60-7.68 (m, 2 H) 7.73 (d, J = 16.01 Hz, 1 H)7.77 (bs, 1 H) 7.83 (dd, J = 8.25, 2.10 Hz, 1 H) 7.93-7.96 (m, 2 H) 19i¹H NMR (400 MHz, MeOH-d4): δ ppm 1.50-1.65 (m, 4 H) 2.05 (dd, J = 13.45,7.20 Hz, 1 H) 2.31 (dd, J = 13.40, 9.30 Hz, 1 H) 2.40 (s, 3 H) 3.05-3.28(m, 2 H) 3.40-3.74 (m, 4 H) 4.07 (dd, J = 9.10, 7.25 Hz, 1 H) 5.79 (s, 1H) 6.42 (d, J = 2.29 Hz, 1 H) 6.54 (d, J = 16.01 Hz, 1 H) 6.91 (q, J =6.72 Hz, 1 H) 7.51 (d, J = 8.25 Hz, 1 H) 7.61-7.75 (m, 5 H) 7.82 (dd, J= 8.30, 2.15 Hz, 1 H) 7.93 (d, J = 2.34 Hz, 1 H) 7.97 (s, 1 H) 19j ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.51-1.66 (m, 4 H) 2.04 (dd, J = 13.50,7.15 Hz, 1 H) 2.31 (dd, J = 13.37, 9.18 Hz, 1 H) 2.40 (s, 3 H) 2.65 (t,J = 7.61 Hz, 2 H) 2.99 (t, J = 7.59 Hz, 2 H) 3.06-3.27 (m, 2 H)3.40-3.78 (m, 4 H) 4.08 (dd, J = 8.98, 7.42 Hz, 1 H) 5.80 (s, 1 H) 6.41(d, J = 2.34 Hz, 1 H) 6.88 (q, J = 6.61 Hz, 1 H) 7.27 (d, J = 7.32 Hz, 1H) 7.35-7.41 (m, 1 H) 7.41-7.51 (m, 3 H) 7.77 (dd, J = 8.27, 2.12 Hz, 1H) 7.88-7.97 (m, 2 H) 19k ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (d, J =3.37 Hz, 4 H) 2.04 (dd, J = 13.40, 7.20 Hz, 1 H) 2.30 (dd, J = 13.35,9.20 Hz, 1 H) 2.40 (s, 3 H) 2.63 (t, J = 7.61 Hz, 2 H) 2.96 (t, J = 7.57Hz, 2 H) 3.03-3.26 (m, 2 H) 3.39-3.76 (m, 4 H) 4.07 (dd, J = 9.03, 7.32Hz, 1 H) 5.78 (s, 1 H) 6.41 (d, J = 2.29 Hz, 1 H) 6.86 (q, J = 6.54 Hz,1 H) 7.34 (d, J = 8.25 Hz, 2 H) 7.46 (d, J = 8.30 Hz, 1 H) 7.52 (d, J =8.25 Hz, 2 H) 7.76 (dd, J = 8.27, 2.12 Hz, 1 H) 7.89-7.92 (m, 2 H) 19l¹H NMR (400 MHz, MeOH-d4): δ ppm 1.45-1.65 (m, 4 H) 2.00-2.09 (m, 1 H)2.30 (dd, J = 13.40, 9.25 Hz, 1 H) 2.40 (s, 6 H) 3.03-3.27 (m, 2 H)3.39-3.76 (m, 4 H) 4.07 (dd, J = 9.10, 7.25 Hz, 1 H), 4.67 (s, 2 H) 5.79(s, 1 H) 6.41 (d, J = 2.25 Hz, 1 H) 6.86 (q, J = 6.64 Hz, 1 H) 7.36-7.53(m, 4 H) 7.77 (dd, J = 8.30, 2.15 Hz, 1 H) 7.91 (d, J = 2.44 Hz, 2 H)19m ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.46-1.69 (m, 4 H) 2.00-2.10 (m, 1H) 2.30 (dd, J = 13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H)3.03-3.27 (m, 2 H) 3.39-3.76 (m, 4 H) 4.07 (dd, J = 9.13, 7.22 Hz, 1 H)4.70 (s, 2 H) 5.78 (s, 1 H) 6.41 (d, J = 2.25 Hz, 1 H) 6.85 (q, J = 6.57Hz, 1 H) 7.26 (d, J = 7.91 Hz, 1 H) 7.43 (dd, J = 7.81, 1.95 Hz, 1 H)7.47 (d, J = 8.30 Hz, 1 H) 7.64 (d, J = 1.81 Hz, 1 H) 7.79 (dd, J =8.27, 2.12 Hz, 1 H) 7.91 (d, J = 2.29 Hz, 1 H) 7.94 (s, 1 H) 19n ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.2 Hz, 1H), 1.56 (d, J = 6.3 Hz,4H), 2.03 (d, J = 12.8 Hz, 1H), 2.30 (d, J = 12.4 Hz, 1H), 2.39 (s, 3H),3.09 (d, J = 11.5 Hz, 1H), 3.22 (d, J = 11.7 Hz, 1H), 3.47 (t, J = 18.6Hz, 2H), 3.63 (s, 2H), 4.07 (s, 1H), 4.64 (s, 1H), 5.78 (s, 1H), 6.41(d, J = 2.1 Hz, 1H), 6.87 (q, J = 6.5 Hz, 1H), 7.44 (m, 4H), 7.59 (d, J= 7.4 Hz, 2H), 7.64 (s, 1H), 7.77 (m, 1H), 7.91 (m, 2H) 19o ¹H NMR (400MHz, MeOH-d4): δ ppm 1.30 (d, J = 18.0 Hz, 1H), 1.57 (d, J = 6.1 Hz,4H), 2.04 (dd, J = 13.9, 6.4 Hz, 1H), 2.30 (dd, J = 13.5, 8.4 Hz, 1H),2.39 (s, 3H), 3.11 (d, J = 11.6 Hz, 1H), 3.23 (d, J = 11.4 Hz, 1H), 3.48(dq, J = 21.6, 7.6, 6.8 Hz, 2H), 3.64 (dd, J = 13.8, 6.9 Hz, 2H), 4.08(m, 1H), 4.87 (s, 12H), 5.78 (s, 1H), 6.41 (d, J = 2.0 Hz, 1H), 6.91 (q,J = 6.6 Hz, 1H), 7.36 (m, 2H), 7.50 (t, J = 9.3 Hz, 2H), 7.74 (dd, J =8.3, 2.2 Hz, 1H), 7.90 (dd, J = 7.9, 2.1 Hz, 2H) 19p ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.27 (s, 1H), 1.44 (s, 1H), 1.52 (q, J = 5.9 Hz, 4H),1.85 (m, 1H), 2.11 (dd, J = 13.2, 8.8 Hz, 1H), 2.39 (s, 3H), 2.77 (d, J= 11.3 Hz, 1H), 3.01 (d, J = 11.3 Hz, 1H), 3.45 (ddt, J = 19.8, 12.8,5.8 Hz, 2H), 3.61 (m, 2H), 3.74 (t, J = 8.0 Hz, 1H), 5.78 (s, 1H), 6.42(d, J = 2.4 Hz, 1H), 6.93 (q, J = 6.6 Hz, 1H), 7.54 (m, 3H), 7.75 (m,2H), 7.92 (dd, J = 11.1, 2.0 Hz, 2H) 19q ¹H NMR (400 MHz, MeOH-d4): δppm 1.28 (s, 1H), 1.57 (t, J = 5.0 Hz, 4H), 2.03 (dd, J = 13.3, 6.9 Hz,1H), 2.29 (dd, J = 13.4, 9.0 Hz, 1H), 2.39 (s, 3H), 3.08 (d, J = 11.6Hz, 1H), 3.22 (d, J = 11.6 Hz, 1H), 3.48 (ddt, J = 20.4, 13.2, 5.9 Hz,2H), 3.65 (dd, J = 13.7, 6.5 Hz, 2H), 4.05 (t, J = 8.0 Hz, 1H), 5.77 (s,1H), 6.41 (d, J = 2.3 Hz, 1H), 6.89 (q, J = 6.6 Hz, 1H), 7.47 (m, 3H),7.58 (m, 2H), 7.77 (dd, J = 8.3, 2.2 Hz, 1H), 7.91 (t, J = 2.4 Hz, 2H)19r ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.94-7.80 (m, 9H), 7.60 (d, J = 8.1Hz, 6H), 7.50 (dd, J = 20.7, 8.1 Hz, 9H), 6.94 (q, J = 6.2 Hz, 3H), 6.42(d, J = 2.3 Hz, 3H), 4.66 (s, 5H), 4.38 (t, J = 8.4 Hz, 3H), 3.73 (s,6H), 3.63-3.55 (m, 1H), 3.29-3.18 (m, 5H), 2.40 (s, 9H), 2.07 (dd, J =13.5, 7.8 Hz, 3H), 1.70-1.61 (m, 10H), 1.28 (s, 1H).

Example 20:(S)-8-(2-amino-6-((R)-1-(2′-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made using the procedure described for(S)-8-(2-amino-6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 5a) starting with(S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J=7.15 Hz, 3H) 1.60 (t, J=5.54Hz, 4H) 2.06 (dd, J=13.50, 7.25 Hz, 1H) 2.33 (dd, J=13.42, 9.27 Hz, 1H)2.40 (s, 3H) 3.08-3.28 (m, 2H) 3.39-3.73 (m, 4H) 3.74-3.98 (m, 2H) 4.08(dd, J=9.08, 7.32 Hz, 1H) 5.74 (s, 1H) 6.42 (d, J=2.34 Hz, 1H) 6.88 (q,J=6.75 Hz, 1H) 7.38 (dd, J=7.71, 0.93 Hz, 1H) 7.45-7.56 (m, 4H)7.58-7.65 (m, 1H) 7.82 (dd, J=7.69, 1.20 Hz, 1H) 7.95 (d, J=2.34 Hz,1H). LCMS (MH+): 680.

Example 21:(S)-8-(2-amino-6-((R)-1-(4′-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made using the procedure described for(S)-8-(2-amino-6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 5) starting with(S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t, J=7.15 Hz, 3H) 1.58 (br. s.,4H) 2.05 (dd, J=13.50, 7.15 Hz, 1H) 2.30 (dd, J=13.42, 9.18 Hz, 1H) 2.40(s, 3H) 3.03-3.28 (m, 2H) 3.37-3.76 (m, 4H) 4.07 (dd, J=9.13, 7.22 Hz,1H) 4.39 (q, J=7.13 Hz, 2H) 5.78 (s, 1H) 6.42 (d, J=2.25 Hz, 1H)6.86-7.01 (m, 1H) 7.53 (d, J=8.30 Hz, 1H) 7.66-7.77 (m, 2H) 7.84 (dd,J=8.30, 2.20 Hz, 1H) 7.94 (d, J=2.29 Hz, 1H) 7.99 (d, J=1.51 Hz, 1H)8.06-8.17 (m, 2H). LCMS (MH+): 680.

Example 22a:(S)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

(S)-Ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(100 mg, 0.171 mmol) in MeOH (2 mL) was hydrogenated via an H-Cubeapparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0mL/min at RT. The catalyst was filtered and the filtrate wasconcentrated in vacuo. The residue was lyophilized from 1:1 H₂O:CH₃CN toprovide (S)-ethyl8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid which was used directly in the next step.

Step 2:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as a whitesolid.

Using the same generic scheme below, the following examples of Table 8acan be prepared as described above for(S)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 22a).

TABLE 8a

Ex. LCMS No. R CAS Name (MH+) 22a

(S)-8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 561 22b

S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-propylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 575 22c

(S)-8-(2-amino-6-((R)-1-(5-butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 589

TABLE 8b NMR Data for Compounds of Table 8a Ex. No. NMR 22a ¹H NMR (400MHz, MeOH-d4): δ ppm 1.24 (t, J = 7.59 Hz, 3 H) 1.57 (m, 4 H) 2.06 (dd,J = 13.42, 7.13 Hz, 1 H) 2.32 (dd, J = 13.45, 9.20 Hz, 1 H) 2.37 (s, 3H) 2.72 (q, J = 7.61 Hz, 2 H) 3.18 (m, 2 H) 3.57 (m, 4 H) 4.08 (dd, J =9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36 (d, J = 2.34 Hz, 1 H) 6.71 (q, J= 6.65 Hz, 1 H) 7.31 (m, 1 H) 7.39 (m, 1 H) 7.56 (s, 1 H) 7.82 (d, J =2.29 Hz, 1 H) 22b ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.91 (t, J = 7.35 Hz,2 H) 1.62 (m, 6 H) 2.06 (dd, J = 13.52, 7.17 Hz, 1 H) 2.31 (dd, J =13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.66 (t, J = 7.52 Hz, 2 H) 3.18 (m, 2H) 3.56 (m, 4 H) 4.08 (dd, J = 9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36(d, J = 2.29 Hz, 1 H) 6.70 (q, J = 6.70 Hz, 1 H) 7.31 (m, 1 H) 7.37 (m,1 H) 7.53 (s, 1 H) 7.82 (d, J = 2.29 Hz, 1 H) 22c ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.92 (t, J = 7.37 Hz, 2 H) 1.32 (dq, J = 14.94, 7.38 Hz,2 H) 1.60 (m, 6 H) 2.06 (dd, J = 13.37, 7.22 Hz, 1 H) 2.31 (dd, J =13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.69 (t, J = 7.59 Hz, 2 H) 3.18 (m, 2H) 3.58 (m, 4 H) 4.08 (dd, J = 9.20, 7.25 Hz, 1 H) 5.75 (s, 1 H) 6.36(d, J = 2.15 Hz, 1 H) 6.69 (q, J = 6.62 Hz, 1 H) 7.30 (m, 1 H) 7.37 (m,1 H) 7.53 (s, 1 H) 7.82 (d, J = 2.29 Hz, 1 H)

Example 23:(S)-8-(2-Amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(S)-8-(2-amino-6-((R)-1-(5-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (product of Step 3, Example 10m) (180 mg, 0.24 mmol) in ethanol (2mL) was added Pd(PPh₃)₂Cl₂ (34 mg, 0.048 mmol), KHCO₃ (242 mg, 2.4mmol). A balloon of CO was fitted and the reaction mixture was heated to80° C. for 20 h, then cooled to RT. The reaction was quenched withwater, and extracted with EtOAc. The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated in vacuo.Purification by normal phase silica gel column (CH₂Cl₂/MeOH/AcOH)provided(S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as an off-white solid.

Step 2:

N-CBZ Deprotection of(S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid was accomplished via Method A to provide the title compound as anoff-white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.34 (t, J=7.10 Hz, 3H) 1.51-1.71 (m,4H) 1.90 (dd, J=13.28, 9.18 Hz, 1H) 2.26-2.40 (m, 4H) 3.13 (br. s., 2H)3.66 (br. s., 4H) 4.29-4.52 (m, 4H) 6.07 (s, 1H) 6.47 (d, J=2.39 Hz, 1H)7.48 (d, J=6.05 Hz, 1H) 7.72 (d, J=8.40 Hz, 1H) 8.15 (dd, J=8.40, 1.95Hz, 1H) 8.19-8.29 (m, 2H) 8.96 (d, J=5.56 Hz, 1H) 10.36 (d, J=4.49 Hz,1H). LCMS (MH+): 604.

Example 24:(S)-8-(2-Amino-6-((R)-1-(5-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

Hydrolysis of(S)-8-(2-amino-6-((R)-1-(5-(ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 23) using the LiOH general method provides the titlecompound as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.45-1.65 (m, 4H) 1.83-1.95 (m, 1H)2.26-2.38 (m, 4H) 3.12 (br. s., 2H) 3.61 (br. s., 4H) 4.36-4.51 (m, 1H)5.93 (br. s., 1H) 6.46 (d, J=2.39 Hz, 1H) 7.40 (m, J=5.80 Hz, 1H) 7.67(d, J=8.35 Hz, 1H) 8.11 (dd, J=8.35, 1.95 Hz, 1H) 8.21 (d, J=2.39 Hz,1H) 8.25 (s, 1H) 8.93 (m, J=4.40 Hz, 1H) 10.09 (br. s., 1H). LCMS (MH+):576.

Example 25:(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(386 mg, 0.50 mmol) in DMF (10 mL) and Et₃N (0.35 mL, 2.5 mmol) wasadded (n-octyl)₃SiH (368 mg, 1.0 mmol). The mixture was degassed under 1atm of CO balloon and PdCl₂(PPh₃)₂ (72 mg, 0.10 mmol) was added, thendegassed again with 1 atm of CO, and heated to 80° C. for 12 h. Thereaction was cooled to RT and concentrated in vacuo. The residue wasdiluted with water then extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo.Normal phase column chromatography on silica gel (EtOAc/heptane)provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a light yellow solid contaminated with about 25% of (S)-2-benzyl3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas by-product. The mixture was used directly in the next step.

Step 2:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(36 mg, 0.05 mmol) in dichloroethane (2 mL) was added NaCNBH₃ (1M inTHF, 1 mL, 0.5 mmol), followed by a few drops of HOAc. The mixture wasstirred at RT for 3 h then concentrated in vacuo. The residue wasdissolved in MeOH and purified on reverse phase HPLC (MeOH/H₂O/HOAc) toprovide (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a sticky solid that was used without further purification.

Step 3:

N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 4:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as a whitesolid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J=5.15 Hz, 4H) 1.91-2.12 (m,7H) 2.30 (dd, J=13.23, 9.42 Hz, 1H) 2.36 (s, 3H) 3.07-3.26 (m, 2H)3.39-3.54 (m, 2H) 3.58-3.70 (m, 2H) 3.99-4.13 (m, 1H) 4.65 (s, 2H) 5.71(s, 1H) 6.37 (d, J=2.34 Hz, 1H) 6.74 (q, J=6.65 Hz, 1H) 7.39 (s, 1H)7.45 (d, J=8.20 Hz, 1H) 7.68 (d, J=8.10 Hz, 1H) 7.84 (d, J=2.34 Hz, 1H).LCMS (MH+): 562.

Example 26:(S)-8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(166 mg, 0.23 mmol, see Ex. 25) in dichloroethane (4 mL) and HOAc (10mg) was added NaBH(OAc)₃ (242 mg, 1.15 mmol) and Me₂NH (2M in THF, 0.58mL, 1.15 mmol). The reaction mixture was stirred at RT for 20 h thenconcentrated in vacuo. The residue was dissolved in MeOH (1 mL) andpurified by reverse phase HPLC (MeOH/H₂O/HOAc) to provide (S)-2-benzyl3-ethyl 8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

N-CBZ Deprotection was accomplished via Method A to provide (S)-ethyl8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as a whitesolid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.66-1.81 (m, 4H) 2.10 (dd, J=13.62,8.54 Hz, 1H) 2.38 (s, 3H) 2.49 (dd, J=13.62, 8.88 Hz, 1H) 2.88 (s, 3H)2.90 (s, 3H) 3.58-3.90 (m, 4H) 4.37-4.49 (m, 2H) 4.56 (t, J=8.69 Hz, 1H)6.37 (br. s., 1H) 6.43 (d, J=2.34 Hz, 1H) 7.06-7.12 (m, 1H) 7.71-7.78(m, 2H) 7.85 (d, J=8.10 Hz, 1H) 7.98 (d, J=2.39 Hz, 1H). LCMS (MH+):589.

Example 27:(S)-8-(6-((R)-1-(4-Bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of 1(R)-1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol(15.7 g, 46.3 mmol, Intermediate 1) in dioxane (200 mL) was added4,6-dichloro-2-methylpyrimidine (30.6 g, 51 mmol) and Cs₂CO₃ (61.2 g,187 mmol). The reaction mixture was heated to 80° C. for 30 h, thencooled to RT, and filtered. The residue was concentrated in vacuo andpurified by normal phase column chromatography on silica gel(CH₂Cl₂/heptane) to provide(R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidineas a white solid.

Step 2:

To a solution of(R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidine(21 g) in dioxane (200 ml) was added (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (15 g) and Na₂CO₃ (14 g).The reaction was heated to 90° C. for 48 h, then cooled to RT, filtered,and concentrated in vacuo. Purification of the residue on normal phasecolumn chromatography on silica gel (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 4:

N-CBZ Deprotection was accomplished via Method A to provide (S)-ethyl8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylatean off-white solid.

Step 5:

Hydrolysis of (S)-ethyl8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as anoff-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.64 (br. s., 4H) 2.10 (d, J=7.03 Hz,1H) 2.28 (s, 3H) 2.35 (dd, J=13.37, 9.27 Hz, 1H) 2.39 (s, 3H) 3.10-3.20(m, 1H) 3.28 (d, J=11.91 Hz, 1H) 3.45-3.67 (m, 2H) 3.75 (br. s., 2H)4.10 (dd, J=8.98, 7.22 Hz, 1H) 6.17 (s, 1H) 6.43 (d, J=2.15 Hz, 1H) 7.01(d, J=6.44 Hz, 1H) 7.58-7.75 (m, 3H) 8.03 (d, J=2.15 Hz, 1H). LCMS(MH+): 609.

Example 28:(S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

The title compound was prepared as described above for(S)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (by replacing 1(R)-1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanolwith1(R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol,Intermediate 3) and obtained as an off-white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.34-1.54 (m, 4H) 1.82 (dd, J=13.01,6.76 Hz, 1H) 1.99-2.08 (m, 1H) 2.11 (s, 3H) 2.30 (s, 3H) 2.92 (d,J=11.52 Hz, 1H) 3.06 (d, J=11.52 Hz, 1H) 3.42-3.65 (m, 4H) 3.70 (dd,J=8.91, 7.00 Hz, 1H) 6.15 (s, 1H) 6.42 (s, 1H) 7.43 (q, J=6.93 Hz, 1H)7.54-7.61 (m, 1H) 7.64 (d, J=2.10 Hz, 1H) 7.70 (d, J=8.44 Hz, 1H) 8.19(d, J=2.39 Hz, 1H) 8.70 (br. s., 1H). LCMS (MH+): 565.

General Biaryl Coupling (Suzuki) Procedures

Biaryl Coupling Method A

Step 1:

To a mixture of(S)-2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (product of Step 3, Example 10m) (150 mg, 0.2 mmol), an arylboronicacid (0.4 mmol), Pd(N,N-dimethyl μ-alaninate)₂ (3.42 mg, 0.01 mmol), andK₃PO₄ (128 mg, 0.6 mmol) were added water (3.0 mL) and EtOH (3.0 mL).The mixture was stirred at 50° C. for 12 h. The reaction was then cooledto RT, diluted with water, and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. The target biaryl compounds were purified by normal phase silicagel column (CH₂Cl₂:MeOH).

Step 2:

Subsequent N-CBZ deprotection via method A afforded the final targetspirocyclic amino acids.

Biaryl Coupling Method B

Step 1:

To a mixture of(S)-2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (product of Step 3, Example 10m) (150 mg, 0.2 mmol), an arylboronicacid (0.4 mmol), Pd(OAc)₂.(1,1,3,3-tetramethyl-2-N-butylguanidine)₂ (5.7mg, 0.01 mmol), and K₂CO₃ (83.5 mg, 0.61 mmol) was added water (1.0 mL)and dioxane (3.0 mL). The reaction mixture was stirred at 44° C. for 24h. The reaction mixture was then cooled to RT, diluted with water, andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo. The target biaryl compoundswere purified by normal phase silica gel column (CH₂Cl₂:MeOH).

Step 2:

Subsequent N-CBZ deprotection via method A afforded the final targetspirocyclic amino acids.

Using the generic scheme below and employing the biaryl coupling methodA, the following examples of Table 9 were prepared.

TABLE 9

Ex. LCMS No. Cy CAS Name (MH+) 29a

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 638 29b

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 686 29c

(S)-8-(6-((R)-1-(3′,4′-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 645 29d

(S)-8-(6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 635 29e

(S)-8-(6-((R)-1-(3′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 680 29f

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 639 29g

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyrimidin-5-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 640 29h

(S)-8-(6-((R)-1-(2′,4′-dimethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 668 29i

(S)-8-(6-((R)-1-(4′-(ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 679 29j

(S)-8-(6-((R)-1-(4′-(dimethylcarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 678 29k

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 639 291

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 655.6 29m

(S)-8-(6-((R)-1-(3′-(dimethylcarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 679

Using the generic scheme above with the biaryl coupling method B, thefollowing examples of Table 10 were prepared.

TABLE 10

Ex. LCMS No. Cy CAS Name (MH+) 29n

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2′,4′,6′-trimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 650 29o

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 666 29p

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid638 29q

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 695 29r

(S)-8-(6-((R)-1-(4′-(tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 663 29s

(S)-8-(6-((R)-1-(4′-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 65229t

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 692 29u

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 666 29v

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 609 29w

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid637 29x

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-isopropyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid650 29y

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid626 29z

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 609 29aa

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid638 29ab

(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 608

Example 30a:8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol(5.00 g, 17.2 mmol) and 4,6-dichloro-2-(methylthio)pyrimidine (3.36 g,17.2 mmol) in dioxane (250 mL) was added Cs₂CO₃ (16.8 g, 51.6 mmol). Thereaction mixture was then heated to 70° C. for 90 h, then cooled to RT.The reaction mixture was quenched with water and extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification on a 120 g IscoRediSep silica cartridge (EtOAc:heptane) provided4-chloro-6-[(R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-2-methylsulfanylpyrimidineas a white solid.

Step 2:

To a solution of4-chloro-6-[(R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-2-methylsulfanylpyrimidine(4 g, 8.95 mmol) in CH₂Cl₂ (200 mL) was added m-CPBA (4.2 g of a 77%(w/w) source, 18.8 mmol) and the reaction was stirred at RT for 15 h.The reaction was then diluted with saturated NaHCO₃, and extracted withCH₂Cl₂. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification on a 120 gIsco RediSep silica cartridge (EtOAc:heptane) provided4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-2-methylsulfonylpyrimidineas an off-white solid.

Step 3:

To a solution of4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-2-methylsulfonylpyrimidine(2.49 g, 5.17 mmol) in dioxane (100 mL) was added 2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.8 g, 5.2 mmol), Cs₂CO₃(5.06 g, 15.5 mmol), and the reaction mixture was heated to 100° C. for1.5 h. The reaction mixture was cooled to RT, quenched with brine, andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification on a 120 gIsco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl3-ethyl8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a whitesolid (1.3 g) in addition to (S)-2-benzyl 3-ethyl8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

Step 4:

To a solution of 2-benzyl 3-ethyl8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(2.10 g, 2.65 mmol) in 2:1 THF:H₂O (90 mL) was added LiOH (127 mg, 5.3mmol), and the reaction was stirred at RT for 21 h, after whichadditional LiOH (65 mg, 2.6 mmol) was added, and the reaction wasstirred for 8 h longer. The reaction was then quenched with 1 N HCl topH<1, and extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated in vacuo to provide2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as an off-white solid which was used directly without furtherpurification.

Step 5:

To a solution of2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (300 mg, 0.393 mmol) in 1,4-dioxane (10 mL) was added phenol (74mg, 0.79 mmol), Cs₂CO₃ (512 mg, 1.5 mmol), and the reaction was heatedto 70° C. for 21 h. The reaction was then cooled to RT, diluted withwater, acidified to pH<1 with 1 N HCl, and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification on a 50 g Isco Gold RediSep reversephase silica cartridge (H₂O:HOAc: 99:1 MeOH:HOAc 99:1) provided2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as an off-white solid.

Step 6:

N-CBZ Deprotection was accomplished via Method B to provide the titlecompound as an off-white solid.

Using the generic scheme below, the following examples of Table 11a wereprepared as described above for8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 30a).

TABLE 11a

Ex. No. R CAS Name LCMS (MH+) 30a

8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxy-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 644 30b

8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2- (cyclohexyloxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 649

TABLE 11b NMR Data for Compounds of Table 11a Ex. No. NMR 30a ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4 H), 2.00-2.31 (m, 2 H), 2.32(s, 3 H), 3.06-3.28 (m, 2 H), 3.36-3.71 (m, 4 H), 4.07 (dd, J = 8.83,7.37 Hz, 1 H), 6.11 (s, 1 H), 6.30 (d, J = 2.34 Hz, 1 H), 6.70 (q, J =6.43 Hz, 1 H), 6.97-7.06 (m, 2 H), 7.10-7.20 (m, 1 H), 7.26-7.36 (m, 2H), 7.47 (d, J = 2.15 Hz, 1 H), 7.54 (dd, J = 8.54, 2.15 Hz, 1 H), 7.71(d, J = 8.54 Hz, 1 H), 7.86 (d, J = 2.39 Hz, 1 H). 30b ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.16-1.95 (m, 14 H), 2.04-2.35 (m, 2 H), 2.36 (s, 3 H),3.07-3.30 (m, 2 H), 3.43-3.82 (m, 4 H), 4.09 (dd, J = 8.86, 7.39 Hz, 1H), 4.80-4.95 (m, 1 H), 5.98 (s, 1 H), 6.37 (d, J = 2.39 Hz, 1 H),7.01-7.13 (m, 1 H), 7.45-7.55 (m, 2 H), 7.70 (d, J = 9.08 Hz, 1 H), 8.12(d, J = 2.34 Hz, 1 H)

Example 31:8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclohexylamino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above by replacing thealcohol in Step 5 of Example 30a with cyclohexyl amine

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.99-1.95 (m, 14H), 2.02-2.37 (m, 2H),2.38 (s, 3H), 3.07-3.29 (m, 2H), 3.41-3.77 (m, 5H), 4.09 (dd, J=9.10,7.15 Hz, 1H), 5.60 (s, 1H), 6.39 (d, J=2.39 Hz, 1H), 6.87-7.21 (m, 1H),7.49 (dtd, J=4.48, 2.26, 2.26, 2.12 Hz, 2H), 7.70 (d, J=9.03 Hz, 1H),7.87 (d, J=2.34 Hz, 1H). LCMS (MH+): 650.

Example 32:(S)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclobutanecarboxamido)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (product of Step 3, Example 10m) (300 mg, 0.412 mmol) in pyridine(1.0 mL) was added cyclobutanecarbonyl chloride (54 mg, 0.045 mmol). Thereaction mixture was stirred at RT for 3 h, then diluted with EtOAc, andwashed with 0.5 N HCl. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification on a 40 g Isco RediSepsilica cartridge (EtOAc/heptane) provides (S)-2-benzyl 3-ethyl8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(cyclobutanecarboxamido)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as anoff-white solid.

Step 2:

The title compound was prepared by the N-CBZ removal using the generalmethod B to provide a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.66 (d, J=4.30 Hz, 4H), 1.78-1.99 (m,2H), 2.03-2.38 (m, 6H), 2.39 (s, 3H), 3.12-3.32 (m, 2H), 3.47-3.90 (m,5H), 4.10 (dd, J=9.10, 7.20 Hz, 1H), 6.03 (s, 1H), 6.41 (d, J=2.34 Hz,1H), 6.82-6.98 (m, 1H), 7.45-7.57 (m, 2H), 7.73 (d, J=8.49 Hz, 1H), 7.97(d, J=2.34 Hz, 1H). LCMS (MH+): 649.

Example 33:(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-oxopyrrolidin-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d) starting with(R)-1-(5-chloro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)pyrrolidin-2-one.

¹H NMR (DMSO-d6): δ ppm 1.23 (m, 1H), 1.40 (m, 4H), 1.81 (dd, J=13.2,6.9 Hz, 1H), 2.07 (m, 4H), 2.45 (d, J=8.1 Hz, 2H), 2.91 (d, J=11.5 Hz,3H), 3.06 (d, J=11.6 Hz, 1H), 3.47 (d, J=6.9 Hz, 3H), 3.66 (m, 3H), 5.54(s, 1H), 6.09 (s, 2H), 6.74 (q, J=6.9 Hz, 1H), 7.55 (m, 3H). LCMS (MH+):570.

Example 34c:(S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol(Intermediate 43) (400 mg, 1.4 mmol) in dioxane (25 mL) was added4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and Cs₂CO₃ (1.3 g, 4mmol). The mixture was heated for 24 h at 80° C. The reaction was thencooled to RT and filtered. The solvent was removed in vacuo, then CH₂Cl₂and heptane was added. The solvent volume was reduced until a solidprecipitated out. The solid was filtered and the procedure repeatedseveral times to provide(R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amineas a white solid.

Step 2:

To a solution of(R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine(100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S)-2-benzyl3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol),and NaHCO₃ (300 mg, 3.5 mmol). After 5 h, an additional amount of NaHCO₃(300 mg, 3.5 mmol) was added and the reaction mixture was heated to 90°C. for 36 h. The reaction was then cooled to RT and filtered.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(100 mg, 0.13 mmol) in 10:1 dioxane:water (5 mL) was phenyl boronic acid(33 mg, 0.27 mmol), KHCO₃ (27 mg, 0.3 mmol), and PdCl₂(dppf)-CH₂Cl₂ (6mg, 0.007 mmol). The reaction was heated to 100° C. for 15 h, cooled toRT, and concentrated in vacuo. The residue was diluted with water, andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 4:

N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylatean off-white solid.

Step 5:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as anoff-white solid as the zwitterionic form.

Example 34u:(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(500 mg, 0.688 mmol) in 10:1 dioxane:water (11 mL) was added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (195mg, 0.7 mmol), KHCO₃ (207 mg, 2.06 mmol), and PdCl₂(dppf)-CH₂Cl₂ (56 mg,0.069 mmol). The reaction was heated to 100° C. for 15 h, cooled to RT,and concentrated in vacuo. The residue was diluted with water, andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 2:

N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as anoff-white solid.

Using the generic scheme below, the following examples of Table 12a canbe prepared as described above for(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34u).

TABLE 12a

Ex. LCMS No. Cy CAS Name (MH+) 34a

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 597 34b

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 34c

8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 563 34d

8-(2-amino-6-((R)-1-(2′-amino-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 34e

8-(2-amino-6-((R)-1-(5-chloro-3′-nitro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 606 34f

8-(2-amino-6-((R)-1-(3′-amino-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 34g

8-(2-amino-6-((R)-1-(5-chloro-4′-nitro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 607 34h

8-(2-amino-6-((R)-1-(4′-amino-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 34i

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(6-methylpyridin-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 578 34j

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(ethylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 655 34k

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(propylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 669 34l

(S)-8-(2-amino-6-((R)-1-(3′-(butylsulfonyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 682 34m

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(hydroxymethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 592 34n

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonamido)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 656 34o

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(2-oxopyrrolidin-1-yl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 646 34p

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(3-methyl-2-oxoimidazolidin-1-yl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 660.5 34q

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 630 34r

(S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 563 34s

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 604 34t

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 566 34u

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 641 34v

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-hydroxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 34w

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 640 34x

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-cyano-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 587 34y

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 592 34z

(S)-8-(2-amino-6-((R)-1-(3′-(aminomethyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 591 34aa

(S)-8-(6-((R)-1-(3′-(acrylamidomethyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 64534ab

(S)-8-(2-amino-6-((R)-1-(3′-carboxy-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 606 34ac

(S)-8-(2-amino-6-((R)-1-(3′-carbamoyl-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 605 34ad

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 640 34ae

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 641 34af

(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 615 34ag

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 621 34ah

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-ethoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 607 34ai

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-ethoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 642 34aj

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 611 34ak

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 655 34al

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-4′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 639 34am

(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 665 34an

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-5′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 615 34ao

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 619 34ap

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-5′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 665 34aq

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-5′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 648 34ar

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 593 34as

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 580 34at

(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 611 34au

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,5′-difluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 598 34av

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 615 34aw

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,4′-difluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 598 34ax

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 665 34ay

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,4′-dimethyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 591 34az

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-ethoxy-3′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 625 34ba

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,5′-dimethyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 591 34bb

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-methyl-4′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 661 34bc

(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-3′,5′-dimethyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 625 34bd

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 595 34be

(S)-8-(2-amino-6-((R)-1-(3′,5-dichloro-5′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 611 34bf

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,4′,5′-trifluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 616 34bg

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 696 34bh

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 698 34bi

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isopropyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 605 34bj

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′,5,5′-trichloro-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 631 34bk

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-fluoro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 648 34bl

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-5′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 639 34bm

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5-chloro-5′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 633 34bn

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 595 34bo

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-3-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 563 34bp

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-ethoxy-4′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 625 34bq

(S)-8-(2-amino-6-((R)-1-(3′-(tert-butyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 619 34br

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(prop-1-en-2-yl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 603 34bs

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-(dimethylamino)pyridin-4-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 603 34bt

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(naphthalen-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 613 34bu

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-isopropylpyridin-4-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 606 34bv

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 525 34bw

(S)-8-(2-amino-6-((R)-1-(4′,5-dichloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 597 34bx

(S)-8-(2-amino-6-((R)-1-(5-chloro-4′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 34by

(S)-8-(2-amino-6-((R)-1-(5-chloro-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 567 34bz

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isobutoxy-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 635 34ca

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 660 34cb

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(cyclopentyloxy)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 647 34cc

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(((1R,4R)-4-hydroxycyclohexyl)carbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 740 34cd

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-ethyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 591 34ce

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-isopropyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 633 34cf

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 703 34cg

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(morpholine-4-carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 676 34ch

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(4-methylpiperazine-1-carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 689 34ci

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-methylthiazol-5-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 584 34cj

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 594 34ck

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(N-methylsulfamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 656 34cl

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(N,N-dimethylsulfamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 670 34cm

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(methylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 620 34cn

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(dimethylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 634 34co

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(diethylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 662 34cp

(S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-4-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 60334cq

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 675 34cr

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(4-cyclopropylpiperazine-1-carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 716 34cs

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyridin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 564 34ct

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyrimidin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 564 34cu

(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 565 34cv

(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(2-methoxyethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 637 *Stereochemistry defined in name in table below

TABLE 12b NMR Data for Compounds of Table 12a Ex. No. NMR 34a ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.31 (d, J = 15.3 Hz, 1H), 1.67 (d, J = 7.3Hz, 4H), 2.10 (dd, J = 13.6, 8.1 Hz, 1H), 2.46 (m, 1H), 3.25 (t, J =12.0 Hz, 2H), 3.52 (s, 2H), 3.63 (m, 3H), 4.45 (t, J = 8.6 Hz, 1H), 4.83(d, J = 3.0 Hz, 1H), 6.59 (q, J = 6.5 Hz, 1H), 7.32 (q, J = 1.8 Hz, 1H),7.39 (m, 1H), 7.52 (m, 4H), 7.70 (d, J = 8.4 Hz, 1H) 34b ¹H NMR (400MHz, MeOH-d4): δ ppm 1.60 (q, J = 5.6 Hz, 4H), 2.06 (dd, J = 13.4, 7.2Hz, 1H), 2.33 (dd, J = 13.5, 9.2 Hz, 1H), 2.43 (s, 3H), 3.13 (d, J =11.8 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.47 (m, 2H), 3.62 (tt, J =9.2, 4.9 Hz, 2H), 4.10 (dd, J = 9.1, 7.1 Hz, 1H), 4.61 (s, 1H), 5.48 (s,1H), 6.66 (q, J = 6.9 Hz, 1H), 7.27 (m, 4H), 7.42 (m, 2H), 7.67 (d, J =8.5 Hz, 1H) 34c ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (d, J = 4.88 Hz, 4H) 2.08 (dd, J = 13.47, 7.22 Hz, 1 H) 2.34 (dd, J = 13.37, 9.27 Hz, 1 H)3.08-3.19 (m, 1H) 3.28 (d, J = 11.71 Hz, 1 H) 3.38-3.56 (m, 2 H) 3.63(d, J = 5.66 Hz, 2 H) 4.11 (dd, J = 8.98, 7.22 Hz, 1 H) 5.51 (s, 1 H)6.66 (d, J = 6.83 Hz, 1 H) 7.30 (d, J = 2.15 Hz, 1 H) 7.41-7.52 (m, 4 H)7.52-7.61 (m, 2 H) 7.69 (d, J = 8.59 Hz, 1 H) 34d ¹H-NMR (400 MHz,MeOH-d4): δ ppm 1.9 (m, 4H), 1.98 (m, 1H), 2.26 (m, 1H), 3.01 (m, 1H),3.17 (m, 1H), 3.48 (m, 2H), 3.60 (m, 2H), 3.95 (m, 1H), 5.53-5.52 (d,1H), 6.26-6.22 (q, 1H), 6.97-6.69 (m, 3H), 7.31-7.17 (m, 2H), 7.47-7.44(m, 1H), 7.74-7.63 (m, 1H) 34e ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.61 (m,4 H), 2.07-2.04 (m, 1 H), 2.37-2.33 (m, 1 H), 3.15-3.12 (d, 1 H, J =11.8 Hz), 3.25 (d, 1 H, J = 11.8 Hz), 3.50-3.47 (m, 2 H), 3.67-3.66 (m,2 H), 4.11-4.07 (t, 1H), 5.58 (s, 1 H), 6.58-6.53 (q, 1 H, J = 6.8 Hz),7.36 (s, 1 H), 7.53-7.51 (d, 1 H, J = 8.4 Hz), 7.70-7.67 (d, 1 H, J =8.0 Hz), 7.82-7.78 (m, 2 H), 8.38-8.36 (d, 1 H, J = 8.0 Hz), 8.58 (s, 1H) 34f ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (m, 4 H), 2.05-2.02 (m, 1H), 2.31-2.30 (m, 1 H), 3.28-3.21 (d, 1 H, J = 11.8 Hz), 3.48-3.46 (m, 2H, J = 11.8 Hz), 3.68-3.51 (m, 2H), 4.08-4.01 (q, 1 H, J = 7.0 Hz), 5.44(s, 1 H), 6.76-6.69 (m, 4 H), 7.26-7.21 (m, 2 H), 7.41-7.40 (d, 1 H, J =8.4 Hz), 7.66-7.64 (d, 1 H, J = 8.4 Hz) 34g ¹H-NMR 400 MHz, MeOH-d4): δppm 1.28 (m, 2H), 1.63 (m 4H), 2.10-2.04 (m, 1H), 2.42-2.36 (m, 1H),3.19-3.16 (d, J = 6.0, 2H), 3.26 (s, 1H), 3.65 (m, 2H), 4.28-4.24 (t, J= 16.0, 1H), 5.58 (s 1H), 6.62-6.57 (m, 1H), 7.37-7.36 (d, J = 4.0, 1H),7.54-7.51 (dd, J = 12.0, 4.0, 1H), 7.72-7.70 (d, J = 8.0, 1H), 7.78-7.76(d, J = 8.0, 2H), 8.43-8.41 (d, J = 8.0, 2H) 34h ¹H-NMR (400 MHz,MeOH-d4): δ ppm 1.29 (m, 2H), 1.58 (m, 4H), 2.07-2.02 (m, 1H), 2.33-2.28(m, 1H), 3.11-3.08 (d, J = 12.0, 1H), 3.24-3.21 (d, J = 12.0, 1H),3.48-3.41 (m, 2H), 3.60-3.55 (m, 2H), 4.08-4.04 (t, J = 16.0, 1H), 5.39(d, J = 2.0, 1H), 6.66-6.63 (m, 1H), ), 6.86-6.84 (d, J = 8.02H),7.19-7.17 (d, J = 8.0, 2H), 7.25-7.24 (d, J = 4.0, 1H), 7.37-7.35 (dd, J= 8.0, 6.0, 1H), 7.63-7.61 (d, J = 8.0, 1H) 34i ¹H NMR (400 MHz,MeOH-d4): δ 7.88 (t, J = 7.68 Hz, 1 H), 7.70 (d, J = 8.52 Hz, 1 H), 7.50(m, 3 H), 7.35 (d, J = 7.76 Hz, 1 H), 6.99 (q, J = 6.96 Hz, 1H), 5.69(s, 1 H), 4.06 (t, J = 7.48 Hz, 2 H), 3.62 (m, 2 H), 3.48 (m, 2 H), 3.22(d, J = 11.64 Hz, 1H), 3.09 (d, J = 11.44 Hz, 1 H), 2.61 (s, 3 H), 2.30(m, 1 H), 2.03 (m, 1H), 1.57 (m, 4 H). 34j ¹H NMR (400 MHz, MeOH-d4): δppm 1.25 (t, J = 7.4 Hz, 3H), 1.63 (m, 4H), 2.11-2.06 (m, 1H), 2.38-2.31(m, 1H), 3.16-3.13 (m, 1H), 3.26 (m, 1H), 3.31 (m, 2H), 3.55-3.50 (m,2H), 3.71-3.64 (m, 2H), 4.11 (M, 1H), 5.61 (s, 1H), 6.63 (m, 1H), 7.36(s, 1H), 7.52-7.50 (m, 1H), 7.71-7.68 (m, 1H), 7.76-7.75 (m, 1H), 7.83(t, J = 7.8 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H) 8.43 (s, 1H) 34k ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.96 (t, J = 12.0, 4H), 1.70-1.62 (m, 8H),2.06 (s, 1H), 2.32 (s, 1H), 3.24 (d, J = 12.0, 1H), 3.50 (s, 2H), 3.67(s, 2H), 4.07 (s, 1H), 4.63 (s, 1H), 5.61 (s, 1H), 6.62 (q, J = 8.0,1H), 7.37 (s, 1H), 7.50 (d, 1H, J = 8.0), 7.79-7.69 (m, 2H), 7.83 (t,1H, J = 8.0), 8.03 (d, 1H, J = 8.0), 8.45 (s, 1H) 34l ¹H NMR (400 MHz,MeOH-d4): δ ppm 8.47 (s, 1 H), 8.03 (d, 1 H), 7.74 (t, 1 H), 7.67 (m, 2H), 7.51-7.49 (d, 1 H), 7.37 (s, 1 H), 6.64-6.59 (q, 1 H), 5.62 (s, 1H), 4.12-4.08 (t, 1 H), 3.67 (m, 2 H), 3.50 (m, 2 H), 3.26 (d, 1 H),3.13 (d, 1 H), 2.35-2.32 (m, 1 H), 2.05 (m, 1 H), 1.63 (m, 6 H), 1.34(q, 2 H), 0.84-0.80 (t, 3 H) 34m ¹H NMR (400 MHz, MeOH-d4): δ ppm7.74-7.66 (m, 2H), 7.48-7.39 (m, 3H), 7.27 (m, 2H), 6.73-6.71 (m, 1H),5.53 (s, 1H), 4.73 (s, 2H), 4.08 (t, J = 7.1 Hz, 1H), 3.63 (m, 2H), 3.47(m, 2H), 3.27-3.24 (m, 1H), 3.14-3.11 (m, 1H), 2.36-2.30 (m, 1H),2.08-2.03 (m, 1H), 1.60 (m, 4H) 34n ¹H NMR (400 MHz, MeOH-d4)δ ppm 7.66(d, 1 H, J = 8.6 Hz), 7.50 (m, 3 H), 7.31 (m, 2 H), 7.24 (d, 1 H, J =8.2 Hz), 6.61 (m, 1 H), 4.21 (m, 1 H), 3.63 (m, 2 H), 3.48 (m, 2 H),3.21 (m, 1 H), 3.18 (m, 1 H), 3.01 (s, 3 H), 2.37 (m, 1 H), 2.07 (m, 1H), 1.62 (m, 4 H) 34o ¹H-NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 1H),7.60-7.67 (m, 2H), 7.52-7.54 (m, 1H), 7.40-7.46 (m, 1H), 7.31-7.31 (m,1H), 7.22-7.24 (m, 1H), 6.61-6.66 (m, 1H), 5.51 (s, 1H), 4.39-4.04 (m,4H), 3.52-3.60 (m, 2H), 3.42-3.50 (m, 2H), 3.15-3.18 (d, 1H), 2.96-2.99(d, 1H), 2.60-2.64 (m, 2H), 2.18-2.28 (m, 3H), 1.96-2.00 (m, 1H),1.58-1.59 (m, 4H) 34p ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.00 (s, 1H),7.56-7.58 (m, 1H), 7.43-7.49 (m, 2H), 7.26-7.27 (m, 2H), 6.97-7.97 (m,1H), 6.59-6.55 (m, 1H), 5.48 (s, 1H), 3.78-3.82 (m, 1H), 3.70-3.74 (m,2H), 3.39-3.44 (m, 6H), 2.98-3.02 (d, 1H), 2.82-2.85 (d, 1H), 2.70 (s,3H), 2.04-2.11 (m, 1H), 1.69-1.75 (m, 1H), 1.36-1.40 (m, 4H) 34q ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.64 (t, J = 5.8 Hz, 4H), 2.08 (dd, J = 13.5,7.6 Hz, 1H), 2.40 (dd, J = 13.5, 9.0 Hz, 1H), 3.19 (d, J = 11.8 Hz, 1H),3.28 (d, J = 12.2 Hz, 1H), 3.51 (m, 2H), 3.66 (m, 2H), 4.28 (t, J = 8.4Hz, 1H), 4.87 (s, 16H), 6.53 (q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.3 Hz,1H), 7.51 (dd, J = 8.6, 2.3 Hz, 1H), 7.75 (m, 5H) 34r ¹H NMR (400 MHz,MeOH-d) δ ppm 1.62 (d, J = 4.88 Hz, 4 H) 2.08 (dd, J = 13.47, 7.22 Hz, 1H) 2.34 (dd, J = 13.37, 9.27 Hz, 1 H) 3.08-3.19 (m, 1H) 3.28 (d, J =11.71 Hz, 1 H) 3.38-3.56 (m, 2 H) 3.63 (d, J = 5.66 Hz, 2 H) 4.11 (dd, J= 8.98, 7.22 Hz, 1 H) 5.51 (s, 1 H) 6.66 (d, J = 6.83 Hz, 1 H) 7.30 (d,J = 2.15 Hz, 1 H) 7.41-7.52 (m, 4 H) 7.52-7.61 (m, 2 H) 7.69 (d, J =8.59 Hz, 1 H) 34s ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (d, J = 5.47 Hz,4 H) 1.98-2.12 (m, 1 H) 2.26-2.39 (m, 1 H) 3.07-3.17 (m, 1 H) 3.20-3.29(m, 1 H) 3.38-3.55 (m, 2 H) 3.56-3.71 (m, 2 H) 4.01-4.15 (m, 1 H) 5.51(s, 1 H) 6.74-6.89 (m, 1 H) 7.11 (s, 1 H) 7.14 (s, 1 H) 7.42 (d, J =2.15 Hz, 11 H) 7.44-7.53 (m, 1 H) 7.61-7.73 (m, 1 H) 34t ¹H NMR (400MHz, MeOH-d4): δ ppm 1.51 (d, J = 4.69 Hz, 4 H) 1.84-2.00 (m, 1 H)2.09-2.31 (m, 1 H) 2.82-3.00 (m, 1 H) 3.02-3.20 (m, 1 H) 3.32-3.64 (m, 4H) 3.84-3.94 (m, 1 H) 3.98 (s, 3 H), 5.50 (s, 1 H) 6.63 (d, J = 1.95 Hz,1 H) 7.13-7.27 (m, 1 H) 7.39 (d, J = 1.56 Hz, 1 H) 7.55 (d, J = 1.76 Hz,1 H) 7.64 (d, J = 8.59 Hz, 1 H) 7.71 (d, J = 1.76 Hz, 1 H) 34u ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.52-1.75 (m, 4 H) 2.07 (dd, J = 13.40, 7.30Hz, 1 H) 2.34 (dd, J = 13.42, 9.18 Hz, 1 H) 3.07-3.29 (m, 2 H) 3.40-3.78(m, 4 H) 4.10 (dd, J = 9.10, 7.25 Hz, 1 H) 5.59 (s, 1 H) 6.61 (q, J =6.59 Hz, 1 H) 7.31 (d, J = 2.20 Hz, 1 H) 7.49 (dd, J = 8.52, 2.22 Hz, 1H) 7.61 (d, J = 7.03 Hz, 1 H) 7.65-7.80 (m, 2 H) 7.97-8.10 (m, 1 H) 8.32(br. s., 1 H) 34v ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.52-1.71 (m, 4 H)2.07 (dd, J = 13.42, 7.27 Hz, 1 H) 2.33 (dd, J = 13.47, 9.27 Hz, 1 H)3.08-3.29 (m, 2 H) 3.36-3.76 (m, 4 H) 4.09 (dd, J = 9.15, 7.20 Hz, 1 H)5.48 (s, 1 H) 6.74 (q, J = 7.00 Hz, 1 H) 6.87 (d, J = 7.47 Hz, 1 H) 6.91(ddd, J = 8.19, 2.48, 0.85 Hz, 1 H) 7.05 (d, J = 0.73 Hz, 1 H) 7.28 (d,J = 2.20 Hz, 1 H) 7.32 (t, J = 7.88 Hz, 1 H) 7.43 (dd, J = 8.49, 2.25Hz, 1 H) 7.67 (d, J = 8.49 Hz, 1 H) 34w ¹H NMR (400 MHz, MeOH-d4): δ ppm1.43-1.76 (m, 4 H) 2.08 (dd, J = 13.45, 7.15 Hz, 1 H) 2.34 (dd, J =13.42, 9.22 Hz, 1 H) 3.13-3.29 (m, 5 H) 3.41-3.77 (m, 4 H) 4.10 (dd, J =9.18, 7.17 Hz, 1 H) 5.60 (s, 1 H) 6.57 (q, J = 6.57 Hz, 1 H) 7.35 (d, J= 2.15 Hz, 1 H) 7.51 (dd, J = 8.52, 2.17 Hz, 1 H) 7.70 (d, J = 8.54 Hz,1 H) 7.72-7.78 (m, 1 H) 7.78-7.87 (m, 1 H) 8.04-8.15 (m, 1 H) 8.41 (d, J= 0.39 Hz, 1 H) 34x ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.46-1.69 (m, 4 H)1.90 (dd, J = 13.25, 9.20 Hz, 1 H) 2.35 (dd, J = 13.35, 8.66 Hz, 1 H)3.14 (br. s., 2 H) 3.64 (br. s., 4 H) 4.45 (t, J = 6.49 Hz, 1 H) 5.84(br. s., 1 H), 6.56 (q, J = 6.77 Hz, 1 H) 7.48 (d, J = 1.07 Hz, 1 H)7.62-7.69 (m, 2 H) 7.75-7.82 (m, 1 H) 7.83-7.91 (m, 1 H) 7.92-8.00 (m, 2H) 8.97 (br. s., 1 H) 10.23 (br. s., 1 H) 34y ¹H NMR (400 MHz, DMSO-d6):δ ppm 1.46-1.71 (m, 4 H) 1.91 (dd, J = 13.32, 9.27 Hz, 1 H) 2.27-2.40(m, 1 H) 3.14 (br. s., 2 H) 3.63 (d, J = 5.37 Hz, 4 H) 3.81 (s, 3 H)4.36-4.53 (m, 1 H) 5.85 (br. s., 1 H) 6.72 (q, J = 6.62 Hz, 1 H)6.94-7.10 (m, 3 H) 7.40 (d, J = 2.05 Hz, 1 H) 7.49 (t, J = 7.96 Hz, 1 H)7.57-7.70 (m, 2 H) 8.96 (d, J = 5.71 Hz, 1 H) 10.27 (br. s., 1 H) 34z ¹HNMR (400 MHz, DMSO-d6): δ ppm 1.43-1.76 (m, 4 H) 1.92 (dd, J = 13.18,9.32 Hz, 1 H) 2.35 (dd, J = 13.30, 8.57 Hz, 1 H) 3.14 (br. s., 2 H) 3.67(br. s., 4 H) 3.97-4.18 (m, 2 H) 4.44 (t, J = 6.88 Hz, 1H) 5.93 (br. s.,1 H) 6.75 (q, J = 6.57 Hz, 1 H) 7.39 (d, J = 1.66 Hz, 1 H) 7.53 (br. s.,1 H) 7.57-7.71 (m, 5 H) 8.58 (br. s., 3 H) 9.01 (br. s., 1 H) 10.55 (br.s., 1 H) 34aa ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.68-1.86 (m, 5 H) 2.13(dd, J = 13.69, 8.66 Hz, 1 H) 2.54 (dd, J = 13.72, 8.98 Hz, 1 H) 3.56(br. s., 1 H) 3.67 (br. s., 3 H) 4.44-4.63 (m, 3 H) 5.70 (dd, J = 9.42,2.54 Hz, 1 H) 6.19-6.35 (m, 2 H) 6.58 (br. s., 1 H) 7.28 (d, J = 7.57Hz, 1 H) 7.34-7.40 (m, 2 H) 7.43 (d, J = 7.86 Hz, 1 H) 7.47-7.56 (m, 2H) 7.71 (d, J = 8.64 Hz, 1 H) 34ab ¹H NMR (400 MHz, DMSO-d6): δ ppm1.44-1.69 (m, 4 H) 1.91 (dd, J = 13.28, 9.18 Hz, 1 H) 2.35 (dd, J =13.15, 8.61 Hz, 1 H) 3.14 (br. s., 2 H) 3.64 (br. s., 4 H) 4.37-4.53 (m,1 H) 5.87 (br. s., 1 H) 6.62 (q, J = 6.78 Hz, 1 H) 7.43 (t, J = 1.22 Hz,1 H) 7.65 (s, 2 H) 7.70 (d, J = 4.78 Hz, 2 H) 7.99-8.12 (m, 1 H) 8.26(br. s., 1 H) 8.96 (d, J = 5.03 Hz, 1 H) 10.25 (br. s., 1 H) 34ac ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.62 (d, J = 4.15 Hz, 4 H) 2.02-2.14 (m, 1 H)2.26-2.43 (m, 1 H) 3.08-3.29 (m, 2 H) 3.40-3.77 (m, 4 H) 4.09 (dd, J =8.98, 7.27 Hz, 1 H) 5.55 (s, 1 H) 6.55-6.70 (m, 1 H) 7.30 (d, J = 2.05Hz, 1 H) 7.47 (dd, J = 8.47, 2.07 Hz, 1 H) 7.51-7.59 (m, 1 H) 7.59-7.65(m, 1 H) 7.67 (d, J = 8.30 Hz, 1 H) 7.96 (dd, J = 8.52, 1.00 Hz, 1 H)8.32-8.50 (m, 1 H) 34ad ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.50-1.76 (m, 4H) 2.07 (dd, J = 13.20, 7.15 Hz, 1 H) 2.34 (dd, J = 13.47, 9.27 Hz, 1 H)3.14 (d, J = 11.71 Hz, 1 H) 3.23 (s, 3 H) 3.27 (d, J = 11.86 Hz, 1 H)3.40-3.76 (m, 4 H) 4.09 (dd, J = 9.03, 7.27 Hz, 1 H) 5.54 (s, 1 H) 6.60(q, J = 6.64 Hz, 1 H) 7.34 (d, J = 2.15 Hz, 1 H) 7.52 (dd, J = 8.49,2.20 Hz, 1 H) 7.72 (d, J = 8.54 Hz, 1 H) 7.78 (d, J = 7.76 Hz, 2 H) 8.14(d, J = 8.64 Hz, 2 H) 34ae ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (q, J =4.88 Hz, 4 H) 2.07 (dd, J = 13.37, 7.13 Hz, 1 H) 2.33 (dd, J = 13.42,9.22 Hz, 1 H) 3.08-3.30 (m, 2 H) 3.38-3.74 (m, 4 H) 4.10 (dd, J = 8.91,7.35 Hz, 1 H), 5.52 (s, 1 H) 6.53-6.69 (m, 1 H) 7.33 (d, J = 2.20 Hz, 1H) 7.50 (dd, J = 8.52, 2.22 Hz, 1 H) 7.67 (d, J = 7.96 Hz, 2 H) 7.71 (d,J = 8.54 Hz, 1 H) 8.08 (d, J = 8.64 Hz, 2 H) 34af ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.62 (q, J = 6.0, 5.0 Hz, 17H), 2.07 (dd, J = 13.4, 7.2Hz, 5H), 2.33 (dd, J = 13.4, 9.2 Hz, 5H), 3.15 (d, J = 11.8 Hz, 5H),3.27 (d, J = 11.8 Hz, 13H), 3.49 (m, 9H), 3.64 (ddt, J = 15.7, 10.7, 5.2Hz, 9H), 4.11 (dd, J = 9.2, 7.1 Hz, 5H), 6.61 (q, J = 6.7 Hz, 4H), 7.33(m, 7H), 7.47 (m, 8H), 7.66 (m, 8H) 34ag ¹H NMR (400 MHz, MeOH-d4): δppm 0.86 (m, 1H), 1.34 (dd, J = 9.4, 6.0 Hz, 7H), 1.58 (t, J = 5.7 Hz,4H), 1.98 (dd, J = 13.3, 7.0 Hz, 1H), 2.26 (dd, J = 13.3, 9.0 Hz, 1H),3.00 (d, J = 11.5 Hz, 1H), 3.16 (d, J = 11.5 Hz, 1H), 3.46 (ddt, J =19.2, 12.6, 5.9 Hz, 2H), 3.62 (dt, J = 12.8, 7.1 Hz, 2H), 3.96 (t, J =8.1 Hz, 1H), 4.69 (p, J = 6.0 Hz, 1H), 5.50 (s, 1H), 6.73 (q, J = 6.9Hz, 1H), 6.95 (m, 1H), 7.04 (dd, J = 8.5, 2.4 Hz, 1H), 7.20 (s, 1H),7.28 (d, J = 2.3 Hz, 1H), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H) 34ah ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.3 Hz, 1H), 1.41 (t, J = 7.0Hz, 3H), 1.61 (q, J = 6.2, 5.4 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, 1H),2.35 (dd, J = 13.5, 9.1 Hz, 1H), 3.14 (d, J = 11.8 Hz, 1H), 3.26 (d, J =11.7 Hz, 1H), 3.33 (s, 1H), 3.48 (m, 2H), 3.66 (dd, J = 14.5, 6.2 Hz,2H), 4.13 (tt, J = 9.7, 7.2 Hz, 3H), 4.87 (s, 17H), 6.74 (q, J = 6.9 Hz,1H), 6.97 (d, J = 7.6 Hz, 1H), 7.04 (dd, J = 8.3, 2.5 Hz, 1H), 7.19 (s,1H), 7.29 (d, J = 2.2 Hz, 1H), 7.44 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H)34ai ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.48 (t, J = 7.0 Hz, 3H), 1.60 (m,4H), 2.06 (dd, J = 13.4, 6.9 Hz, 1H), 2.33 (dd, J = 13.4, 8.9 Hz, 1H),3.13 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 11.4 Hz, 1H), 3.48 (ddd, J =21.0, 14.2, 7.2 Hz, 2H), 3.64 (q, J = 8.9, 8.1 Hz, 2H), 4.09 (t, J = 8.3Hz, 1H), 4.20 (q, J = 6.9 Hz, 2H), 4.88 (s, 15H), 5.52 (s, 1H), 6.63 (q,J = 6.7 Hz, 1H), 7.24 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 7.43 (dd, J =8.5, 2.3 Hz, 2H), 7.57 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H) 34aj ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.58 (dd, J = 7.1, 4.1 Hz, 4H),1.99 (dd, J = 13.4, 7.1 Hz, 1H), 2.29 (m, 1H), 2.46 (s, 3H), 3.02 (d, J= 11.6 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 3.46 (ddt, J = 21.0, 13.5,6.0 Hz, 2H), 3.63 (m, 2H), 3.98 (dd, J = 9.2, 7.1 Hz, 1H), 5.52 (s, 1H),6.60 (q, J = 6.6 Hz, 1H), 7.28 (m, 2H), 7.45 (dd, J = 8.3, 2.4 Hz, 2H),7.56 (m, 1H), 7.66 (d, J = 8.5 Hz, 1H) 34ak ¹H NMR (400 MHz, MeOH-d4): δppm 1.29 (d, J = 6.2 Hz, 1H), 1.40 (d, J = 6.0 Hz, 6H), 1.60 (d, J = 5.2Hz, 4H), 2.03 (dd, J = 13.4, 6.8 Hz, 1H), 2.30 (dd, J = 13.3, 8.9 Hz,1H), 2.81 (s, 1H), 3.07 (d, J = 11.6 Hz, 1H), 3.22 (d, J = 11.8 Hz, 1H),3.48 (m, 2H), 3.64 (d, J = 9.7 Hz, 2H), 4.03 (t, J = 7.9 Hz, 1H), 4.75(m, 1H), 5.53 (s, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.29 (m, 3H), 7.43 (dd,J = 8.6, 2.3 Hz, 1H), 7.58 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H) 34al ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.39 (d, J = 6.0 Hz, 6H), 1.60 (m, 4H), 2.06(dd, J = 13.5, 7.2 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.13 (d, J= 11.7 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.48 (m, 2H), 3.64 (q, J =12.4, 10.4 Hz, 2H), 4.10 (dd, J = 9.2, 7.2 Hz, 1H), 4.70 (hept, J = 5.9Hz, 1H), 5.53 (s, 1H), 6.67 (q, J = 6.8 Hz, 1H), 7.25 (m, 4H), 7.43 (dd,J = 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H) 34am ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (s, 1H), 1.61 (q, J = 5.7 Hz, 4H), 2.06 (dd, J =13.4, 7.1 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.12 (d, J = 11.7Hz, 1H), 3.26 (d, J = 11.6 Hz, 1H), 3.48 (ddt, J = 18.1, 13.6, 6.0 Hz,2H), 3.65 (tt, J = 11.7, 4.8 Hz, 2H), 4.08 (dd, J = 9.2, 7.1 Hz, 1H),5.54 (s, 1H), 6.49 (q, J = 6.6 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.51(dd, J = 8.5, 2.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.82 (td, J = 17.6,16.6, 4.9 Hz, 3H) 34an ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.8Hz, 1H), 1.29 (d, J = 6.7 Hz, 2H), 1.62 (q, J = 5.9, 5.4 Hz, 4H), 2.07(dd, J = 13.4, 7.2 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.13 (d, J= 11.7 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.49 (ddd, J = 21.4, 12.5,5.9 Hz, 2H), 3.65 (td, J = 12.3, 10.3, 5.5 Hz, 2H), 4.10 (dd, J = 9.2,7.1 Hz, 1H), 5.55 (s, 1H), 6.59 (q, J = 6.7 Hz, 1H), 7.25 (d, J = 14.9Hz, 1H), 7.35 (m, 2H), 7.44 (s, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H),7.69 (d, J = 8.5 Hz, 1H) 34ao ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m,2H), 1.30 (d, J = 11.8 Hz, 3H), 1.36 (s, 10H), 1.60 (m, 5H), 2.34 (s,1H), 2.81 (s, 1H), 3.14 (d, J = 11.6 Hz, 1H), 3.28 (m, 4H), 3.45 (s,2H), 3.62 (s, 3H), 4.15 (t, J = 8.1 Hz, 1H), 4.85 (s, 38H), 6.62 (t, J =6.7 Hz, 1H), 7.28 (m, 2H), 7.46 (m, 5H), 7.66 (d, J = 8.5 Hz, 1H) 34ap¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.5 Hz, 2H), 1.65 (s, 3H),2.08 (dd, J = 13.5, 7.9 Hz, 1H), 2.44 (t, J = 11.2 Hz, 1H), 3.24 (dd, J= 14.0, 11.6 Hz, 1H), 3.61 (m, 4H), 4.41 (t, J = 8.4 Hz, 1H), 6.48 (q, J= 6.6 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.5, 2.2 Hz, 1H),7.71 (d, J = 8.6 Hz, 1H), 7.86 (t, J = 1.5 Hz, 2H) 34aq ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (d, J = 2.2 Hz, 1H), 1.60 (s, 4H), 2.03 (d, J =13.1 Hz, 1H), 2.30 (t, J = 11.1 Hz, 1H), 3.08 (d, J = 11.6 Hz, 1H), 3.23(d, J = 12.3 Hz, 1H), 3.50 (dt, J = 24.2, 8.0 Hz, 2H), 3.64 (d, J = 10.2Hz, 2H), 4.03 (t, J = 7.8 Hz, 1H), 4.58 (s, 1H), 5.55 (s, 1H), 6.52 (q,J = 6.7 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.5, 2.3 Hz,1H), 7.66 (m, 4H) 34ar ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (q, J =7.9, 6.6 Hz, 4H), 1.92 (dd, J = 13.2, 7.0 Hz, 1H), 2.19 (dd, J = 13.2,9.0 Hz, 1H), 2.88 (d, J = 11.4 Hz, 1H), 3.10 (d, J = 11.4 Hz, 1H), 3.45(ddt, J = 20.3, 13.1, 6.1 Hz, 2H), 3.61 (m, 2H), 3.87 (s, 4H), 5.48 (s,1H), 6.70 (q, J = 6.9 Hz, 1H), 7.04 (m, 2H), 7.16 (s, 1H), 7.29 (d, J =2.2 Hz, 1H), 7.45 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H) 34as ¹H NMR (400MHz, MeOH-d4): δ ppm 1.29 (d, J = 10.0 Hz, 2H), 1.61 (d, J = 5.6 Hz,5H), 2.06 (dd, J = 13.4, 7.2 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H),3.13 (d, J = 11.7 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.49 (dt, J =21.9, 7.2 Hz, 3H), 3.65 (ddt, J = 15.1, 10.1, 5.2 Hz, 3H), 4.09 (dd, J =9.2, 7.1 Hz, 1H), 4.86 (s, 26H), 5.53 (s, 1H), 6.64 (q, J = 6.8 Hz, 1H),7.28 (m, 5H), 7.47 (dd, J = 8.5, 2.3 Hz, 1H), 7.55 (m, 1H), 7.68 (d, J =8.5 Hz, 1H) 34at ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.35 (s,1H), 1.60 (q, J = 5.1 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz, 1H), 2.30(dd, J = 13.4, 9.1 Hz, 1H), 2.45 (s, 3H), 3.08 (d, J = 11.6 Hz, 1H),3.23 (d, J = 11.7 Hz, 1H), 3.31 (s, 3H), 3.47 (ddt, J = 19.8, 12.7, 5.7Hz, 2H), 3.63 (dt, J = 12.9, 7.5 Hz, 2H), 4.04 (dd, J = 9.0, 7.3 Hz,1H), 5.51 (s, 1H), 6.62 (q, J = 6.8 Hz, 1H), 7.30 (m, 3H), 7.45 (dd, J =8.5, 2.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H)34au ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 6.2 Hz, 1H), 1.62 (q,J = 5.5 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, 1H), 2.35 (dd, J = 13.5,9.2 Hz, 1H), 3.15 (d, J = 11.8 Hz, 1H), 3.27 (d, J = 11.7 Hz, 1H), 3.49(ddt, J = 21.6, 13.6, 6.3 Hz, 2H), 3.66 (ddt, J = 15.6, 10.1, 4.9 Hz,2H), 4.14 (dd, J = 9.1, 7.3 Hz, 1H), 4.85 (d, J = 3.1 Hz, 16H), 6.63 (q,J = 6.8 Hz, 1H), 7.12 (m, 3H), 7.34 (d, J = 2.2 Hz, 1H), 7.50 (dd, J =8.5, 2.2 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H) 34av ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.88 (m, 1H), 1.28 (s, 3H), 1.61 (q, J = 6.1 Hz, 4H),2.07 (dd, J = 13.4, 7.1 Hz, 1H), 2.33 (dd, J = 13.5, 9.0 Hz, 1H), 3.13(d, J = 11.6 Hz, 1H), 3.26 (d, J = 11.8 Hz, 2H), 3.48 (ddt, J = 20.7,12.7, 5.7 Hz, 2H), 3.65 (q, J = 8.9, 6.2 Hz, 2H), 4.10 (m, 1H), 4.90 (s,1H), 5.55 (s, 1H), 6.57 (q, J = 6.8 Hz, 1H), 7.42 (m, 5H), 7.67 (d, J =8.3 Hz, 2H) 34aw ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J = 7.7 Hz,2H), 1.60 (q, J = 6.1, 4.9 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz, 1H),2.30 (dd, J = 13.4, 9.0 Hz, 1H), 3.07 (d, J = 11.6 Hz, 1H), 3.22 (d, J =11.6 Hz, 1H), 3.48 (ddt, J = 20.9, 13.3, 5.7 Hz, 2H), 3.64 (tt, J =10.8, 5.3 Hz, 2H), 4.03 (t, J = 8.1 Hz, 1H), 4.87 (s, 17H), 5.54 (s,1H), 6.61 (q, J = 6.7 Hz, 1H), 7.32 (t, J = 5.0 Hz, 2H), 7.46 (m, 3H),7.54 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H) 34ax ¹H NMR (400 MHz, MeOH-d4): δppm 1.30 (dd, J = 17.9, 6.7 Hz, 2H), 1.54 (m, 4H), 1.79 (dd, J = 12.9,7.0 Hz, 1H), 2.06 (td, J = 16.5, 14.8, 7.8 Hz, 1H), 2.66 (d, J = 11.0Hz, 1H), 2.97 (d, J = 11.1 Hz, 1H), 3.45 (ddt, J = 20.1, 13.2, 6.0 Hz,2H), 3.62 (m, 3H), 5.50 (d, J = 16.5 Hz, 1H), 6.54 (q, J = 6.7 Hz, 1H),7.34 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 8.5, 2.3 Hz, 1H), 7.68 (dd, J =24.2, 8.1 Hz, 2H), 7.84 (m, 1H), 7.97 (d, J = 8.1 Hz, 1H) 34ay ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.28 (s, 2H), 1.40 (s, 10H),1.60 (q, J = 5.5 Hz, 4H), 2.06 (dd, J = 13.5, 7.1 Hz, 1H), 2.35 (d, J =3.7 Hz, 7H), 3.13 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 11.6 Hz, 1H), 3.47(dq, J = 22.4, 7.8, 6.8 Hz, 2H), 3.63 (dd, J = 13.9, 7.3 Hz, 2H), 4.11(t, J = 8.3 Hz, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.17 (d, J = 7.1 Hz, 2H),7.26 (m, 2H), 7.41 (dd, J = 8.5, 2.2 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H)34az ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (q, J = 10.5, 8.0 Hz, 1H),1.30 (d, J = 12.4 Hz, 4H), 1.46 (t, J = 7.0 Hz, 5H), 1.61 (d, J = 5.7Hz, 8H), 2.06 (dd, J = 13.4, 7.1 Hz, 2H), 2.33 (dd, J = 13.3, 8.8 Hz,2H), 3.13 (d, J = 11.5 Hz, 2H), 3.26 (d, J = 11.8 Hz, 2H), 3.48 (m, 4H),3.62 (d, J = 12.9 Hz, 3H), 4.19 (m, 5H), 4.84 (s, 2H), 6.67 (q, J = 6.7Hz, 2H), 7.27 (m, 7H), 7.43 (dd, J = 8.6, 2.2 Hz, 2H), 7.65 (d, J = 8.5Hz, 2H) 34ba ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (m, 4H), 2.04 (dd, J= 13.4, 7.2 Hz, 1H), 2.38 (s, 7H), 3.08 (d, J = 11.7 Hz, 1H), 3.23 (d, J= 11.7 Hz, 1H), 3.46 (m, 2H), 3.64 (dt, J = 14.7, 5.8 Hz, 2H), 4.04 (dd,J = 9.2, 7.1 Hz, 1H), 5.48 (s, 1H), 6.67 (q, J = 6.9 Hz, 1H), 7.03 (s,2H), 7.12 (s, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.5, 2.3 Hz,1H), 7.66 (d, J = 8.5 Hz, 1H) 34bb ¹H NMR (400 MHz, MeOH-d4): δ ppm1.28(s, 3H), 1.58 (m, 4H), 1.98 (dd, J = 13.2, 7.1 Hz, 1H), 2.25 (dd, J =13.3, 9.1 Hz, 1H), 2.40 (s, 3H), 2.98 (d, J = 11.5 Hz, 1H), 3.17 (d, J =11.5 Hz, 1H), 3.46 (ddt, J = 20.0, 13.0, 6.1 Hz, 2H), 3.63 (dq, J =12.7, 6.3 Hz, 2H), 3.95 (dd, J = 9.1, 7.0 Hz, 1H), 4.89 (s, 17H), 5.52(s, 1H), 6.61 (q, J = 6.7 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.46 (m,4H), 7.67 (d, J = 8.4 Hz, 1H) 34bc ¹H NMR (400 MHz, MeOH-d4): δ ppm0.88(d, J = 7.5 Hz, 1H), 1.28 (s, 3H), 1.60 (q, J = 5.5 Hz, 4H), 2.05 (dd, J= 13.6, 7.3 Hz, 1H), 2.30 (m, 1H), 2.44 (d, J = 2.6 Hz, 6H), 3.10 (d, J= 11.7 Hz, 1H), 3.26 (m, 2H), 3.47 (ddd, J = 16.0, 12.4, 6.6 Hz, 2H),3.62 (d, J = 12.7 Hz, 2H), 4.06 (dd, J = 9.2, 7.2 Hz, 1H), 5.50 (d, J =2.5 Hz, 1H), 6.64 (q, J = 6.7 Hz, 1H), 7.21 (s, 2H), 7.27 (d, J = 2.3Hz, 1H), 7.44 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H) 34bd¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 7.7 Hz, 1H), 1.29 (d, J =5.9 Hz, 5H), 1.61 (q, J = 5.6 Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, 1H),2.33 (m, 4H), 2.84 (s, 1H), 3.12 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 11.7Hz, 1H), 3.48 (m, 2H), 3.64 (ddt, J = 15.0, 10.2, 5.1 Hz, 2H), 4.08 (dd,J = 9.2, 7.1 Hz, 1H), 5.52 (s, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.26 (m,4H), 7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H) 34be ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.58 (m, 4H), 1.99 (dd, J =13.3, 7.1 Hz, 1H), 2.27 (dd, J = 13.3, 9.1 Hz, 1H), 2.42 (s, 3H), 3.01(d, J = 11.6 Hz, 1H), 3.19 (d, J = 11.5 Hz, 1H), 3.47 (ddt, J = 21.2,13.6, 6.9 Hz, 2H), 3.64 (dq, J = 12.3, 5.8 Hz, 2H), 3.98 (dd, J = 9.1,7.1 Hz, 1H), 5.52 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H), 7.18 (s, 1H), 7.31(m, 3H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H) 34bf¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.6 Hz, 1H), 1.29 (d, J =7.9 Hz, 4H), 1.62 (s, 8H), 2.09 (d, J = 6.9 Hz, 1H), 2.34 (t, J = 10.9Hz, 2H), 3.15 (d, J = 8.2 Hz, 2H), 3.25 (m, 1H), 3.32 (s, 2H), 3.48 (s,4H), 3.54 (s, 1H), 3.66 (s, 5H), 4.12 (s, 2H), 5.56 (s, 1H), 6.60 (q, J= 6.7 Hz, 2H), 7.34 (m, 5H), 7.50 (dd, J = 8.6, 2.2 Hz, 2H), 7.68 (d, J= 8.5 Hz, 2H) 34bg ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.30(d, J = 14.2 Hz, 7H), 1.61 (s, 12H), 2.07 (m, 3H), 2.36 (dd, J = 13.3,8.3 Hz, 3H), 2.80 (s, 1H), 3.15 (d, J = 11.8 Hz, 3H), 3.26 (d, J = 11.5Hz, 3H), 3.46 (d, J = 16.1 Hz, 5H), 3.52 (d, J = 7.0 Hz, 2H), 3.64 (s,7H), 4.18 (s, 3H), 4.92 (s, 1H), 4.98 (s, 1H), 6.58 (q, J = 6.7 Hz, 3H),7.33 (d, J = 2.0 Hz, 3H), 7.47 (m, 12H), 7.67 (m, 6H) 34bh ¹H NMR (400MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.4 Hz, 1H), 1.29 (d, J = 4.7 Hz, 2H),1.62 (q, J = 6.3, 5.4 Hz, 4H), 2.07 (dd, J = 13.4, 7.3 Hz, 1H), 2.36(dd, J = 13.5, 9.1 Hz, 1H), 3.15 (d, J = 11.8 Hz, 1H), 3.26 (m, 1H),3.50 (ddd, J = 20.3, 10.5, 6.5 Hz, 2H), 3.65 (m, 2H), 4.16 (t, J = 8.2Hz, 1H), 4.68 (s, 1H), 4.95 (t, J = 11.4 Hz, 1H), 6.40 (q, J = 6.5 Hz,1H), 7.41 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.5, 2.3 Hz, 1H), 7.71 (d,J = 8.6 Hz, 1H), 8.12 (s, 3H) 34bi ¹H NMR 400 MHz, MeOH-d4): δ ppm 0.89(d, J = 6.7 Hz, 1H), 1.15 (s, 1H), 1.28 (m, 9H), 1.57 (d, J = 6.4 Hz,5H), 1.92 (dt, J = 13.9, 6.8 Hz, 1H), 2.21 (dd, J = 13.2, 9.1 Hz, 1H),2.95 (m, 2H), 3.11 (d, J = 11.4 Hz, 1H), 3.44 (ddt, J = 20.6, 13.0, 6.2Hz, 2H), 3.60 (dd, J = 13.8, 6.6 Hz, 2H), 3.87 (dd, J = 9.0, 7.0 Hz,1H), 5.46 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H), 7.39 (m, 6H), 7.66 (d, J =8.5 Hz, 1H) 34bj ¹H NMR400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 5.0 Hz,3H), 1.55 (m, 6H), 1.82 (dd, J = 12.9, 6.9 Hz, 1H), 2.10 (dd, J = 13.0,9.0 Hz, 1H), 2.71 (d, J = 11.1 Hz, 1H), 3.00 (d, J = 11.1 Hz, 1H), 3.32(s, 3H), 3.45 (tt, J = 13.0, 6.3 Hz, 3H), 3.65 (ddd, J = 18.3, 10.9, 7.1Hz, 4H), 4.88 (s, 17H), 5.53 (s, 2H), 6.54 (q, J = 6.6 Hz, 1H), 7.32 (d,J = 2.3 Hz, 1H), 7.51 (m, 5H), 7.59 (t, J = 1.9 Hz, 1H), 7.70 (d, J =8.5 Hz, 1H) 34bk ¹H NMR (400 MHz, MeOH-d4): δ ppm1.28 (s, 1H), 1.62 (q,J = 5.5 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, 1H), 2.35 (dd, J = 13.6,9.1 Hz, 1H), 3.15 (d, J = 11.8 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.49(ddt, J = 21.5, 14.0, 6.1 Hz, 2H), 3.65 (m, 2H), 4.15 (dd, J = 9.1, 7.4Hz, 1H), 6.49 (q, J = 6.6 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.52 (m,2H), 7.68 (d, J = 8.5 Hz, 1H), 7.81 (s, 2H) 34bl ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.33 (m, 8H), 1.56 (q, J = 5.9, 5.2 Hz, 4H), 1.89 (dd, J= 13.1, 7.0 Hz, 1H), 2.18 (dd, J = 13.1, 9.0 Hz, 1H), 2.86 (d, J = 11.3Hz, 1H), 3.08 (d, J = 11.4 Hz, 1H), 3.46 (ddd, J = 15.1, 12.2, 6.6 Hz,2H), 3.61 (dd, J = 13.4, 6.0 Hz, 2H), 3.82 (dd, J = 9.0, 7.0 Hz, 1H),4.68 (hept, J = 6.0 Hz, 1H), 5.51 (s, 1H), 6.72 (q, J = 8.2, 7.0 Hz,2H), 6.82 (dt, J = 11.1, 2.3 Hz, 1H), 7.02 (s, 1H), 7.28 (d, J = 2.2 Hz,1H), 7.44 (dd, J = 8.5, 2.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H) 34bm ¹HNMR (400 MHz, MeOH-d4): δ ppm1.32 (d, J = 18.8 Hz, 11H), 1.60 (q, J =5.8 Hz, 4H), 2.05 (dd, J = 13.5, 7.2 Hz, 1H), 2.33 (m, 2H), 2.43 (s,3H), 3.12 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 11.7 Hz, 1H), 3.45 (ddt, J= 21.7, 13.4, 6.5 Hz, 2H), 3.62 (dq, J = 11.4, 5.5 Hz, 2H), 4.09 (dd, J= 9.2, 7.2 Hz, 1H), 6.64 (q, J = 6.8 Hz, 1H), 7.05 (s, 1H), 7.26 (m,2H), 7.34 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d,J = 8.5 Hz, 1H) 34bm ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 2H), 1.53(t, J = 6.1 Hz, 4H), 1.80 (dd, J = 13.0, 6.9 Hz, 1H), 2.09 (dd, J =13.0, 8.9 Hz, 1H), 2.36 (d, J = 2.0 Hz, 3H), 2.68 (d, J = 10.8 Hz, 1H),2.98 (d, J = 11.1 Hz, 1H), 3.42 (m, 2H), 3.63 (m, 3H), 5.49 (s, 1H),6.64 (q, J = 6.8 Hz, 1H), 7.24 (m, 3H), 7.43 (m, 2H), 7.67 (d, J = 8.5Hz, 1H) 34bo 1H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 13.0 Hz, 1H),1.53 (m, 4H), 1.79 (dd, J = 12.9, 6.9 Hz, 1H), 2.08 (dd, J = 12.9, 8.9Hz, 1H), 2.66 (d, J = 11.1 Hz, 1H), 2.97 (d, J = 11.0 Hz, 1H), 3.42 (m,3H), 3.62 (m, 3H), 5.50 (d, J = 15.0 Hz, 1H), 6.53 (q, J = 6.9 Hz, 1H),7.36 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H), 7.63 (dd, J =8.0, 5.0 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.98 (m, 1H), 8.67 (m, 1H),8.74 (s, 1H) 34bp ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t, J = 6.9 Hz,3H), 1.65 (dt, J = 10.9, 5.8 Hz, 4H), 2.08 (dd, J = 13.6, 8.2 Hz, 1H),2.44 (dd, J = 13.6, 8.9 Hz, 1H), 3.24 (m, 2H), 3.57 (m, 4H), 4.13 (qd, J= 7.0, 4.1 Hz, 2H), 4.42 (t, J = 8.5 Hz, 1H), 6.66 (q, J = 6.7 Hz, 1H),7.00 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.28 (m, 2H), 7.46 (dd, J = 8.5,2.3 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H) 34bq ¹H NMR (400 MHz, MeOH-d4): δppm 1.36 (s, 1H), 1.59 (q, J = 5.8, 4.7 Hz, 0H), 2.05 (dd, J = 13.4, 7.2Hz, 0H), 2.31 (m, 0H), 3.12 (d, J = 11.6 Hz, 0H), 3.24 (d, J = 11.7 Hz,0H), 3.42 (d, J = 9.4 Hz, 0H), 3.49 (m, 0H), 3.59 (d, J = 12.4 Hz, 0H),4.09 (dd, J = 9.1, 7.1 Hz, 0H), 4.90 (s, 2H), 5.44 (s, 0H), 6.65 (q, J =7.0 Hz, 0H), 7.27 (m, 0H), 7.45 (m, 0H), 7.54 (s, 0H), 7.69 (m, 0H) 34br¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.7 Hz, 3H), 1.59 (m, 6H),2.04 (dd, J = 13.5, 7.0 Hz, 1H), 2.19 (s, 2H), 2.31 (dd, J = 13.5, 9.2Hz, 1H), 3.11 (d, J = 11.5 Hz, 1H), 3.24 (d, J = 11.8 Hz, 1H), 3.34 (s,1H), 3.47 (dt, J = 24.1, 8.0 Hz, 2H), 3.63 (m, 2H), 4.07 (t, J = 7.9 Hz,1H), 4.73 (s, 1H), 5.16 (m, 1H), 5.47 (d, J = 10.8 Hz, 2H), 6.62 (q, J =6.8 Hz, 1H), 7.33 (m, 1H), 7.51 (m, 3H), 7.68 (d, J = 8.6 Hz, 1H) 34bs¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.60 (q, J = 5.9, 5.4 Hz,4H), 2.04 (m, 1H), 2.31 (dd, J = 13.5, 9.2 Hz, 1H), 3.11 (s, 7H), 3.24(d, J = 11.6 Hz, 1H), 3.47 (m, 2H), 3.63 (s, 2H), 4.06 (t, J = 8.1 Hz,1H), 5.50 (s, 1H), 6.69 (m, 3H), 7.34 (d, J = 2.2 Hz, 1H), 7.48 (dd, J =8.6, 2.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 5.2 Hz, 1H)34bt ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.56 (t, J = 5.4 Hz, 4H), 1.99(dd, J = 13.3, 7.0 Hz, 1H), 2.26 (dd, J = 13.3, 9.1 Hz, 1H), 3.01 (d, J= 11.5 Hz, 1H), 3.18 (d, J = 11.5 Hz, 1H), 3.43 (ddt, J = 20.5, 13.2,6.0 Hz, 2H), 3.60 (dd, J = 13.4, 5.7 Hz, 2H), 3.98 (dd, J = 9.1, 7.0 Hz,1H), 4.85 (m, 1H), 5.47 (s, 1H), 6.68 (q, J = 6.7 Hz, 1H), 7.39 (d, J =2.3 Hz, 1H), 7.54 (m, 4H), 7.72 (d, J = 8.5 Hz, 1H), 7.97 (m, 4H) 34bu¹H NMR (400 MHz, CDCl₃): δ ppm 1.36 (dd, J = 6.9, 3.7 Hz, 6H), 1.73 (dd,J = 13.1, 6.7 Hz, 1H), 2.05 (dd, J = 13.1, 8.8 Hz, 1H), 2.81 (d, J =10.5 Hz, 1H), 2.94 (d, J = 10.5 Hz, 1H), 3.14 (p, J = 6.9 Hz, 1H), 3.47(dt, J = 12.2, 5.6 Hz, 4H), 3.85 (dd, J = 8.8, 6.7 Hz, 1H), 4.19 (q, J =7.1 Hz, 2H), 4.34 (s, 2H), 5.42 (s, 1H), 6.53 (q, J = 6.7 Hz, 1H), 7.25(m, 3H), 7.42 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 8.65(dd, J = 5.0, 0.8 Hz, 1H) 34bv ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d,J = 13.8 Hz, 1H), 1.54 (q, J = 6.0, 5.4 Hz, 4H), 1.80 (dd, J = 13.0, 6.9Hz, 1H), 2.08 (dd, J = 12.8, 8.9 Hz, 1H), 2.66 (d, J = 11.2 Hz, 1H),2.97 (d, J = 11.1 Hz, 1H), 3.38 (m, 3H), 3.61 (dt, J = 13.8, 7.1 Hz,3H), 5.49 (d, J = 1.5 Hz, 1H), 6.60 (q, J = 6.7 Hz, 1H), 7.28 (m, 3H),7.47 (m, 3H), 7.66 (d, J = 8.4 Hz, 1H) 34bw ¹H NMR (400 MHz, MeOH-d4): δppm 1.63 (d, J = 7.6 Hz, 4H), 2.07 (dd, J = 13.4, 7.6 Hz, 1H), 2.39 (dd,J = 13.6, 9.0 Hz, 1H), 3.17 (d, J = 11.9 Hz, 1H), 3.28 (m, 2H), 3.51(dt, J = 23.6, 8.6 Hz, 2H), 3.62 (d, J = 14.5 Hz, 2H), 4.25 (t, J = 8.4Hz, 1H), 6.60 (q, J = 6.6 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.51 (m,6H), 7.66 (d, J = 8.7 Hz, 1H) 34bx ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61(m, 4H), 2.06 (dd, J = 13.5, 7.5 Hz, 1H), 2.39 (m, 4H), 3.15 (d, J =11.8 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.47 (m, 2H), 3.62 (ddd, J =15.6, 9.4, 5.2 Hz, 2H), 4.18 (dd, J = 9.1, 7.4 Hz, 1H), 6.64 (q, J = 6.7Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.38 (m, 4H), 7.65 (d, J = 8.5 Hz,1H) 34by ¹H NMR (400 MHz, MeOH-d4): δ ppm: 1.30 (d, J = 17.9 Hz, 1H),1.58 (q, J = 4.3, 2.7 Hz, 4H), 1.78 (m, 4H), 1.98 (dd, J = 13.3, 7.1 Hz,1H), 2.24 (m, 4H), 2.41 (m, 1H), 3.02 (d, J = 11.6 Hz, 1H), 3.18 (d, J =11.6 Hz, 1H), 3.47 (m, 2H), 3.62 (dq, J = 12.8, 5.9 Hz, 2H), 3.98 (dd, J= 9.1, 7.0 Hz, 1H), 5.49 (s, 1H), 5.75 (q, J = 2.6, 1.7 Hz, 1H), 6.94(q, J = 6.9 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.5, 2.3Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H) 34bz ¹H NMR (400 MHz, MeOH-d4): δ ppm1.02 (m, 7H), 1.28 (d, J = 5.2 Hz, 1H), 1.60 (q, J = 6.1, 5.6 Hz, 4H),2.06 (ddt, J = 14.1, 11.3, 6.7 Hz, 2H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H),3.12 (d, J = 11.7 Hz, 1H), 3.27 (d, J = 25.3 Hz, 3H), 3.47 (ddt, J =20.4, 13.1, 5.7 Hz, 2H), 3.65 (m, 2H), 3.81 (m, 2H), 4.08 (dd, J = 9.1,7.3 Hz, 1H), 5.51 (s, 1H), 6.71 (q, J = 6.8 Hz, 1H), 7.01 (m, 2H), 7.18(s, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.43 (m, 2H), 7.66 (d, J = 8.6 Hz,1H) 34ca ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.00 (t, J = 7.3 Hz, 1H), 1.28(m, 1H), 1.60 (m, 5H), 1.97 (m, 5H), 2.30 (t, J = 11.2 Hz, 1H), 2.83 (t,J = 7.4 Hz, 1H), 3.07 (d, J = 11.5 Hz, 1H), 3.22 (d, J = 11.4 Hz, 1H),3.54 (m, 8H), 4.04 (d, J = 8.7 Hz, 1H), 5.08 (s, 1H), 5.56 (s, 1H), 6.69(q, J = 6.6 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.48 (m, 2H), 7.65 (m,3H), 7.93 (s, 1H) 34cb ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H),1.62 (m, 6H), 1.90 (m, 8H), 2.32 (dd, J = 13.4, 9.1 Hz, 1H), 3.11 (d, J= 11.7 Hz, 1H), 3.25 (d, J = 11.6 Hz, 1H), 3.47 (ddt, J = 21.4, 13.3,6.4 Hz, 2H), 3.65 (dq, J = 13.0, 6.2 Hz, 2H), 4.08 (dd, J = 9.1, 7.1 Hz,1H), 5.51 (s, 1H), 6.72 (q, J = 6.9 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H),7.02 (dd, J = 8.2, 2.6 Hz, 1H), 7.18 (s, 1H), 7.28 (d, J = 2.3 Hz, 1H),7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H) 34cc ¹H NMR (400 MHz, MeOH-d4): δppm 1.29 (m, 1H), 1.49 (m, 8H), 2.02 (m, 5H), 2.33 (dd, J = 13.3, 9.0Hz, 1H), 3.13 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 12.3 Hz, 1H), 3.58(ddd, J = 32.1, 26.0, 15.3 Hz, 5H), 3.88 (td, J = 10.6, 10.2, 3.9 Hz,1H), 4.08 (t, J = 8.1 Hz, 1H), 5.56 (s, 1H), 6.63 (q, J = 6.7 Hz, 1H),7.29 (d, J = 2.2 Hz, 1H), 7.56 (m, 4H), 7.89 (d, J = 7.7 Hz, 1H), 8.34(s, 1H) 34cd ¹H NMR (400 MHz, MeOH-d4): δ ^(ppm) 1.28 (q, J = 7.6, 6.7Hz, 4H), 1.57 (p, J = 3.8 Hz, 4H), 1.99 (dd, J = 13.3, 7.1 Hz, 1H), 2.27(dd, J = 13.3, 9.1 Hz, 1H), 2.73 (q, J = 7.6 Hz, 2H), 3.01 (d, J = 11.5Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 3.45 (ddt, J = 21.2, 13.1, 5.9 Hz,2H), 3.60 (dt, J = 12.5, 6.8 Hz, 2H), 3.98 (dd, J = 9.1, 7.1 Hz, 1H),4.93 (s, 11H), 5.47 (s, 1H), 6.64 (q, J = 6.8 Hz, 1H), 7.30 (m, 4H),7.43 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H) 34ce ¹H NMR (400 MHz, MeOH-d4): δppm 1.28 (m, 9H), 1.52 (ddd, J = 11.5, 7.0, 4.8 Hz, 4H), 1.74 (dd, J =13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J = 10.9Hz, 1H), 2.95 (m, 2H), 3.50 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H),4.18 (qd, J = 7.1, 1.5 Hz, 2H), 4.92 (s, 8H), 5.47 (d, J = 14.2 Hz, 1H),6.61 (q, J = 6.8 Hz, 1H), 7.32 (m, 4H), 7.44 (m, 2H), 7.66 (d, J = 8.5Hz, 1H) 34cf ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.09 (s, 0H), 0.89 (t, J =6.5 Hz, 0H), 1.31 (d, J = 12.8 Hz, 1H), 1.59 (m, 0H), 1.84 (s, 0H), 2.02(d, J = 6.4 Hz, 0H), 2.19 (t, J = 7.8 Hz, 0H), 2.65 (s, 0H), 2.76 (t, J= 6.7 Hz, 0H), 2.87 (d, J = 14.6 Hz, 0H), 3.06 (s, 0H), 3.30 (s, 1H),3.49 (m, 0H), 3.61 (m, 0H), 3.82 (s, 0H), 4.98 (s, 0H), 5.33 (m, 0H),5.55 (s, 0H), 7.30 (s, 0H), 7.38 (d, J = 7.9 Hz, 0H), 7.46 (t, J = 7.3Hz, 0H), 7.54 (t, J = 7.8 Hz, 0H), 7.64 (m, 0H), 7.81 (t, J = 8.6 Hz,0H), 7.93 (m, 0H), 8.40 (s, 0H) 34cg ¹H NMR (400 MHz, MeOH-d4): δ ppm1.73 (p, J = 7.2, 6.3 Hz, 4H), 2.10 (dd, J = 13.7, 8.5 Hz, 1H), 2.50(dd, J = 13.6, 8.9 Hz, 1H), 3.26 (m, 4H), 3.61 (m, 11H), 3.78 (d, J =16.7 Hz, 4H), 4.53 (t, J = 8.7 Hz, 1H), 6.61 (m, 1H), 7.36 (d, J = 2.2Hz, 1H), 7.58 (m, 6H) 34ch ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.43 (m,4H), 1.79 (dd, J = 13.3, 7.5 Hz, 1H), 2.13 (m, 1H), 2.30 (s, 3H), 2.48(m, 3H), 2.95 (d, J = 11.8 Hz, 1H), 3.09 (m, 1H), 3.38 (s, 1H), 3.44 (s,6H), 3.66 (s, 2H), 3.82 (t, J = 8.3 Hz, 1H), 5.54 (s, 1H), 6.57 (q, J =6.8 Hz, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.55 (m, 6H) 34ci ¹H NMR (400MHz, MeOH-d4): δ ppm 1.29 (d, J = 4.2 Hz, 2H), 1.59 (m, 5H), 1.99 (dd, J= 13.4, 6.9 Hz, 1H), 2.27 (dd, J = 13.3, 8.9 Hz, 1H), 2.80 (s, 3H), 3.01(d, J = 11.5 Hz, 1H), 3.18 (d, J = 11.4 Hz, 1H), 3.48 (m, 3H), 3.62 (q,J = 6.8, 5.6 Hz, 2H), 3.98 (t, J = 8.0 Hz, 1H), 5.52 (s, 1H), 6.75 (q, J= 6.7 Hz, 1H), 7.49 (m, 3H), 7.69 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H) 34cj¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.58 (s, 8H), 2.06 (dd, J= 10.2, 6.4 Hz, 2H), 2.30 (m, 2H), 3.12 (s, 2H), 3.23 (d, J = 9.6 Hz,2H), 3.49 (m, 4H), 3.64 (s, 9H), 4.07 (t, J = 7.9 Hz, 2H), 5.64 (s, 1H),6.24 (d, J = 7.2 Hz, 2H), 6.50 (t, J = 6.8 Hz, 2H), 7.31 (d, J = 2.2 Hz,2H), 7.46 (dd, J = 14.7, 7.7 Hz, 3H), 7.65 (d, J = 8.5 Hz, 2H), 7.78(dd, J = 12.8, 6.1 Hz, 2H) 34ck ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62(q, J = 6.1, 5.6 Hz, 4H), 2.06 (dd, J = 13.4, 7.2 Hz, 1H), 2.34 (dd, J =13.5, 9.2 Hz, 1H), 2.58 (s, 3H), 3.13 (d, J = 11.7 Hz, 1H), 3.26 (d, J =11.7 Hz, 2H), 3.51 (m, 2H), 3.68 (td, J = 14.8, 14.3, 7.0 Hz, 2H), 4.08(dd, J = 9.2, 7.1 Hz, 1H), 4.87 (d, J = 7.3 Hz, 1H), 4.97 (s, 1H), 5.60(s, 1H), 6.65 (q, J = 6.6 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.50 (dd, J= 8.6, 2.2 Hz, 1H), 7.67 (dd, J = 12.0, 8.0 Hz, 2H), 7.77 (t, J = 7.8Hz, 1H), 7.94 (dt, J = 7.9, 1.4 Hz, 1H), 8.31 (s, 1H) 34cl ¹H NMR (400MHz, MeOH-d4): δ ppm 1.61 (d, J = 5.5 Hz, 5H), 2.04 (dd, J = 13.3, 7.1Hz, 1H), 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 2.73 (s, 6H), 3.08 (d, J =11.6 Hz, 1H), 3.23 (d, J = 11.7 Hz, 1H), 3.53 (m, 2H), 3.68 (d, J = 14.2Hz, 2H), 4.04 (dd, J = 9.1, 7.0 Hz, 1H), 5.62 (s, 1H), 6.69 (q, J = 6.6Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 8.5, 2.3 Hz, 1H), 7.70(dd, J = 12.4, 7.7 Hz, 2H), 7.86 (m, 2H), 8.33 (s, 1H) 34cm ¹H NMR (400MHz, MeOH-d4): δ ppm 1.27 (s, 1H), 1.57 (p, J = 7.6, 6.8 Hz, 4H), 1.86(dd, J = 13.0, 6.9 Hz, 1H), 2.15 (dd, J = 13.2, 9.0 Hz, 1H), 2.81 (d, J= 11.2 Hz, 1H), 2.95 (s, 4H), 3.05 (d, J = 11.2 Hz, 1H), 3.32 (s, 1H),3.46 (ddt, J = 17.4, 13.1, 5.7 Hz, 2H), 3.62 (dq, J = 11.5, 5.5 Hz, 2H),3.76 (dd, J = 9.0, 6.9 Hz, 1H), 5.54 (s, 1H), 6.63 (q, J = 6.7 Hz, 1H),7.29 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.62 (m, 3H),7.89 (dt, J = 7.7, 1.5 Hz, 1H), 8.36 (s, 1H) 34cn ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (s, 2H), 1.62 (q, J = 5.7, 5.0 Hz, 12H), 2.07 (dd,J = 13.4, 7.1 Hz, 3H), 2.35 (dd, J = 13.4, 9.1 Hz, 3H), 3.09 (d, J =26.8 Hz, 23H), 3.26 (s, 2H), 3.53 (m, 6H), 3.64 (d, J = 13.0 Hz, 7H),4.15 (s, 3H), 4.88 (d, J = 3.3 Hz, 1H), 4.97 (s, 1H), 5.56 (s, 1H), 6.71(q, J = 6.7 Hz, 3H), 7.32 (d, J = 2.2 Hz, 3H), 7.56 (m, 15H), 7.78 (s,3H) 34co ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.13 (t, J = 7.1 Hz, 3H), 1.26(m, 4H), 1.61 (q, J = 6.1, 5.6 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, 1H),2.33 (dd, J = 13.4, 9.3 Hz, 1H), 3.13 (d, J = 11.7 Hz, 1H), 3.47 (m,10H), 4.09 (t, J = 8.3 Hz, 1H), 5.55 (s, 1H), 6.74 (q, J = 6.8 Hz, 1H),7.32 (d, J = 2.2 Hz, 1H), 7.48 (m, 3H), 7.65 (m, 3H) 34cp ¹H NMR (400MHz, MeOH-d4): δ ppm 1.28 (m, 7H), 1.58 (d, J = 13.6 Hz, 14H), 2.05 (m,3H), 2.31 (s, 4H), 2.88 (s, 1H), 3.11 (d, J = 12.1 Hz, 3H), 3.25 (d, J =12.8 Hz, 3H), 3.38 (s, 10H), 3.48 (s, 3H), 3.63 (m, 5H), 4.09 (t, J =8.2 Hz, 3H), 4.48 (s, 2H), 4.98 (s, 3H), 5.10 (s, 1H), 5.42 (s, 2H),5.54 (s, 2H), 6.50 (d, J = 13.3 Hz, 2H), 6.79 (m, 1H), 7.22 (s, 2H),7.44 (s, 5H), 7.53 (d, J = 8.4 Hz, 5H), 7.76 (s, 7H), 8.11 (m, 3H) 34cq¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (s, 3H), 1.62 (s, 8H), 2.08 (dd, J= 13.3, 7.1 Hz, 2H), 2.35 (t, J = 11.4 Hz, 2H), 3.16 (d, J = 11.8 Hz,2H), 3.32 (m, 23H), 3.49 (s, 4H), 3.63 (d, J = 19.6 Hz, 3H), 3.83 (s,4H), 3.90 (s, 2H), 3.97 (s, 2H), 4.05 (s, 1H), 4.13 (t, J = 7.7 Hz, 2H),6.67 (m, 2H), 7.35 (s, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.66 (dq, J =31.2, 9.5, 9.1 Hz, 7H), 7.84 (s, 2H) 34cr ¹H NMR (400 MHz, MeOH-d4): δppm 0.46 (m, 4H), 1.28 (s, 1H), 1.58 (s, 4H), 1.69 (d, J = 7.3 Hz, 1H),1.97 (d, J = 9.1 Hz, 1H), 2.24 (dd, J = 13.1, 9.0 Hz, 1H), 2.58 (s, 2H),2.73 (s, 2H), 2.96 (d, J = 11.3 Hz, 1H), 3.15 (d, J = 11.6 Hz, 1H), 3.32(m, 1H), 3.48 (t, J = 12.1 Hz, 4H), 3.63 (s, 2H), 3.76 (s, 2H), 3.92 (t,J = 8.1 Hz, 1H), 5.55 (s, 1H), 6.71 (q, J = 6.7 Hz, 1H), 7.33 (d, J =2.2 Hz, 1H), 7.50 (m, 3H), 7.66 (m, 2H), 7.80 (s, 1H) 34cl ¹H NMR (400MHz, MeOH-d4): δ ppm 8.71 (d, J = 4.7 Hz, 1H), 8.02 (t, J = 7.9 Hz, 1H),7.72 (t, J = 7.3 Hz, 2H), 7.52 (d, J = 10.9 Hz, 3H), 6.92 (d, J = 6.7Hz, 1H), 5.87 (s, 1H), 4.80 (s, 7H), 4.10 (d, J = 8.7 Hz, 1H), 3.66 (s,2H), 3.50 (s, 2H), 3.30 (s, 5H), 3.25 (d, J = 11.8 Hz, 1H), 3.12 (d, J =11.7 Hz, 1H), 2.35-2.27 (m, 1H), 2.06 (dd, J = 13.3, 7.1 Hz, 1H), 1.59(s, 3H), 1.59 (d, J = 11.4 Hz, 1H) 34cm ¹H NMR (400 MHz, MeOH-d4): δ ppm8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, 1H), 7.75 (d, J = 9.4 Hz, 2H),7.60-7.49 (m, 2H), 5.71 (s, 1H), 4.10 (s, 1H), 3.59 (d, J = 18.5 Hz,2H), 3.30 (d, J = 3.1 Hz, 9H), 3.11 (d, J = 12.0 Hz, 1H), 2.31 (t, J =11.6 Hz, 1H), 2.06 (s, 1H), 1.57 (s, 5H), 1.28 (s, 1H) 34cu ¹H NMR (400MHz, MeOH-d4): δ ppm 8.96 (d, J = 1.5 Hz, 1H), 8.83-8.77 (m, 1H), 8.71(d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.64-7.55 (m, 2H), 6.87(q, J = 6.7 Hz, 1H), 5.64 (s, 1H), 3.99 (t, J = 8.2 Hz, 1H), 3.46 (s,1H), 3.19 (d, J = 11.6 Hz, 1H), 3.03 (d, J = 11.6 Hz, 1H), 2.27 (dd, J =13.3, 9.2 Hz, 1H), 2.00 (dd, J = 13.4, 7.0 Hz, 1H), 1.57 (s, 3H), 1.29(s, 1H). 34cv ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.67 (d, J = 8.5 Hz, 2H),7.44 (ddd, J = 8.0, 4.8, 2.6 Hz, 3H), 7.32-7.23 (m, 3H), 7.07 (dd, J =8.4, 2.6 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.0 Hz, 2H),4.26-4.05 (m, 5H), 3.75 (t, J = 4.7 Hz, 3H), 3.42 (s, 4H), 3.36 (s, 1H),3.26 (d, J = 11.7 Hz, 3H), 3.13 (d, J = 11.7 Hz, 2H), 2.33 (dd, J =13.5, 9.1 Hz, 2H), 2.06 (dd, J = 13.4, 7.1 Hz, 2H), 1.61 (d, J = 5.6 Hz,5H).

Example 35:(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(2′-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 20) starting with(S)-8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid.

1H NMR (400 MHz, DMSO-d6): δ ppm 1.29-1.38 (m, 3H) 1.47-1.72 (m, 4H)1.91 (dd, J=13.28, 9.18 Hz, 1H) 2.35 (dd, J=13.25, 8.61 Hz, 1H) 3.14(br. s., 2H) 3.65 (br. s., 4H) 4.30-4.40 (m, 2H) 4.40-4.50 (m, 1H) 5.90(br. s., 1H) 6.59 (q, J=6.67 Hz, 1H) 7.11 (br. s., 1H) 7.44 (t, J=1.22Hz, 1H) 7.66 (s, 2H) 7.70-7.79 (m, 2H) 8.08 (dt, J=6.37, 2.14 Hz, 1H)8.14 (br. s., 1H) 8.98 (d, J=5.61 Hz, 1H) 10.36 (d, J=5.08 Hz, 1H). LCMS(MH+): 634.

Example 36:(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d) starting with(R)-1-(4-bromo-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol andobtained as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.44-1.66 (m, 4H) 1.83-1.95 (m, 1H)2.34 (dd, J=13.08, 8.79 Hz, 1H) 3.14 (br. s., 2H) 3.33 (s, 3H) 3.42-3.65(m, 4H) 3.67-3.79 (m, 2H) 4.19-4.27 (m, 1H) 4.27-4.36 (m, 1H) 4.48 (t,J=6.49 Hz, 1H) 5.74 (s, 1H) 6.99 (q, J=6.78 Hz, 1H) 7.07-7.16 (m, 1H)7.27 (s, 1H) 7.43 (d, J=8.35 Hz, 1H) 8.93 (d, J=5.42 Hz, 1H) 9.81 (br.s., 1H). LCMS (MH+): 560.

Example 36b:(S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol(1 g, 3.5 mmol) and 1H-benzo[d]imidazole (408 mg, 3.5 mmol) in toluene(24 mL) was added sequentially, CuI (131 mg, 0.69 mmol), K₂CO₃ (1.19 g,8.63 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (196 mg,1.38 mmol). The reaction mixture was purged with N₂ and then heated at130° C. in a sealed tube for 12 h. Afterward, the reaction was cooled toRT. The solid was removed by filtration and the filtrate wasconcentrated and purified by flash column (EtOAc in hexane=0 to 50%) toafford—(R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethanolas a white solid.

Steps 2-5:

The title compound was made as described for Example 10d (Steps 1-4) toprovide a white solid.

1H NMR (400 MHz, DMSO-d6): δ ppm 1.59 (m, 4H), 2.05 (dt, J=13.7, 6.9 Hz,1H), 2.33 (dt, J=14.5, 8.5 Hz, 1H), 3.13 (dd, J=11.7, 7.6 Hz, 1H), 3.26(m, 2H), 3.49 (m, 3H), 3.63 (m, 2H), 4.10 (q, J=7.0, 5.2 Hz, 1H), 5.48(d, J=3.9 Hz, 1H), 6.43 (p, J=6.4 Hz, 1H), 7.22 (dd, J=7.8, 4.0 Hz, 1H),7.38 (m, 2H), 7.61 (dd, J=5.3, 2.2 Hz, 1H), 7.81 (m, 3H), 8.54 (s, 1H).LCMS (MH⁺): 603.

Example 36c:(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(1H-indazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(6-((R)-1-(2-(1H-benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 36b) starting with 1H-indazole and obtained as a whitesolid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, 5H), 2.05 (dd, J=13.4, 7.1 Hz,1H), 2.32 (dd, J=13.5, 9.2 Hz, 1H), 3.12 (d, J=11.7 Hz, 1H), 3.24 (d,J=11.7 Hz, 1H), 3.52 (dddd, J=44.5, 25.8, 14.0, 7.1 Hz, 5H), 4.13 (dd,J=9.1, 7.1 Hz, 1H), 4.92 (s, 1H), 6.68 (q, J=6.5 Hz, 1H), 7.31 (t, J=7.4Hz, 1H), 7.46 (m, 2H), 7.72 (m, 5H), 8.39 (s, 1H). LCMS (MH⁺): 603.

Example 36d:(S)-8-(2-amino-6-((R)-1-(4-bromo-2-(piperazin-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

A mixture of 4-bromo-2-fluorobenzoic acid (2 g, 9.1 mmol), benzylpiperazine-1-carboxylate (2.4 g, 10.9 mmol) and K₂CO₃ (2.5 g, 18.26mmol) in DMF (40 mL) was stirred at 150° C. for 36 h. The reaction wasthen cooled to RT and extracted with ethyl acetate, 3 N HCl, brine,dried over Na₂SO₄, filtered and concentrated in vacuo to provide2-(4-((benzyloxy) carbonyl)piperazin-1-yl)-4-bromobenzoic acid as yellowoil that was used without further purification.

Step 2:

To a mixture of 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-4-bromobenzoic acid (2 g, 9.1 mmol) in THF (20mL) was added dropwise BH₃/THF (1.0 M, 40 mL) at 0° C. The mixture wasrefluxed for 2 h, then cooled to RT, quenched with H₂O, and extractedwith ethyl acetate, 3 N HCl, brine, then dried over Na₂SO₄, filtered andconcentrated. Purification by normal phase silica gel (ethylacetate/hexanes) provided benzyl4-(5-bromo-2-(hydroxymethyl)phenyl)piperazine-1-carboxylate as a whitesolid.

Steps 3-10:

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 54d) following Steps 4-11.

¹H NMR (MeOH-d4): δ ppm 0.90 (dt, J=16.0, 8.0 Hz, 1H), 1.31 (s, 2H),1.62 (t, J=5.6 Hz, 5H), 2.03 (dd, J=13.6, 6.9 Hz, 1H), 2.30 (dd, J=13.4,9.1 Hz, 1H), 2.76 (dd, J=10.1, 6.3 Hz, 2H), 3.08 (m, 8H), 3.22 (d,J=11.6 Hz, 1H), 3.47 (s, 1H), 3.54 (m, 1H), 3.65 (dd, J=13.9, 6.8 Hz,2H), 4.01 (t, J=8.0 Hz, 1H), 5.56 (s, 1H), 7.31 (q, J=6.9 Hz, 1H), 7.41(dd, J=8.4, 1.9 Hz, 1H), 7.50 (m, 2H). LCMS (MH+): 615.

Example 36e:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared starting with (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(intermediate from Step 8, Example 36d] via a Suzuki coupling with(4-isopropoxyphenyl)boronic acid as described for example 54b.

¹H NMR (MeOH-d4): δ ppm 0.90 (m, 1H), 1.33 (m, 8H), 1.40 (s, 1H), 1.59(q, J=5.7 Hz, 4H), 2.06 (dd, J=13.7, 7.0 Hz, 1H), 2.31 (dd, J=13.5, 9.2Hz, 1H), 3.11 (m, 3H), 3.26 (d, J=11.7 Hz, 1H), 3.51 (m, 10H), 4.09 (dd,J=9.3, 6.8 Hz, 1H), 4.64 (p, J=6.0 Hz, 1H), 5.56 (s, 1H), 6.98 (m, 2H),7.32 (q, J=7.0 Hz, 1H), 7.53 (m, 4H), 7.64 (d, J=8.2 Hz, 1H). LCMS(MH+): 671.

Example 36f:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-morpholino-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 36e) substituting morpholine for benzylpiperazine-1-carboxylate.

¹H NMR (MeOH-d4): δ ppm 1.32 (d, J=6.0 Hz, 7H), 1.58 (d, J=6.0 Hz, 4H),1.98 (m, 1H), 2.25 (dd, J=13.3, 9.0 Hz, 1H), 2.83 (m, 2H), 2.99 (d,J=11.5 Hz, 1H), 3.19 (m, 3H), 3.32 (s, 1H), 3.48 (ddt, J=18.5, 8.9, 5.0Hz, 2H), 3.62 (s, 2H), 3.92 (m, 5H), 4.63 (h, J=6.0 Hz, 1H), 4.88 (m,1H), 5.54 (s, 1H), 6.97 (m, 2H), 7.41 (m, 2H), 7.54 (m, 4H). LCMS (MH+):672

Example 36g:(S)-8-(6-((R)-1-([1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34u) starting with1-(2-bromophenyl)-2,2,2-trifluoroethanone.

¹H NMR (MeOH-d4): δ ppm 1.58 (d, J=5.4 Hz, 4H), 2.00 (dd, J=13.4, 7.1Hz, 1H), 2.27 (dd, J=13.3, 9.2 Hz, 1H), 3.02 (d, J=11.6 Hz, 1H), 3.19(d, J=11.5 Hz, 1H), 3.30 (q, J=1.8 Hz, 3H), 3.45 (td, J=14.5, 6.3 Hz,1H), 3.61 (m, 2H), 3.99 (m, 1H), 5.46 (s, 1H), 6.67 (q, J=6.8 Hz, 1H),7.26 (dd, J=6.2, 2.4 Hz, 1H), 7.45 (m, 7H), 7.70 (d, J=7.3 Hz, 1H). LCMS(MH+): 528.

Example 37:(3S)-8-(6-(((1r,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

A solution of adamantan-1-yl-methanol (100 mg, 0.60 mmol) in THF (5 mL)was cooled to 0° C. 15-Crown-5 ether (99 mg, 0.5 mmol) and NaH (60% inoil, 92 mg, 2.4 mmol) were added sequentially. The reaction was warmedto RT for 1 h, cooled to 0° C., and 4,6-dichloropyrimidin-2-ylamine (247mg, 1.5 mmol) was added. The reaction was heated to 65° C. for 16 h,cooled to RT, quenched with water, and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by normal phasechromatography (EtOAc/heptane) provided4-(adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine as a white solid.

Step 2:

4-(Adamantan-1-ylmethoxy)-6-chloro-pyrimidin-2-ylamine (89 mg, 0.30mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(157 mg, 0.45 mmol) and NaHCO₃ (76 mg, 0.9 mmol) were dissolved indioxane (1.5 mL) and heated to 95° C. for 64 h. Then the reaction wascooled to RT, quenched with water, and extracted with EtOAc. The organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by normal phase silica gel column(EtOAc/heptane) provides (S)-2-benzyl 3-ethyl8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 4:

Hydrolysis of (S)-ethyl8-(6-(adamantan-1-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provides the title compound as a whitesolid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.12 (d, J=6.25 Hz, 3H) 1.42-1.76 (m,17H) 1.82-2.02 (m, 4H) 2.34 (dd, J=13.32, 8.59 Hz, 1H) 3.12 (br. s., 2H)3.67 (br. s., 4H) 4.35-4.48 (m, 1H) 5.85 (br. s., 1H) 8.97 (br. s., 1H)10.44 (br. s., 1H). LCMS (MH+): 456.

Example 38:(S)-8-(6-((1r,3r,5S,7S)-adamantan-2-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made as described above for(3S)-8-(6-(1-((1r,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 37) using (1r,3r,5r,7r)-adamantan-2-ylmethanol.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.39-1.76 (m, 16H) 1.83-2.01 (m, 4H)2.34 (dd, J=13.18, 8.44 Hz, 1H) 3.13 (br. s., 2H) 3.69 (br. s., 4H) 3.79(s, 2H) 4.42 (br. s., 1H) 5.83 (br. s., 1H) 8.97 (br. s., 1H) 10.40 (br.s., 1H). LCMS (MH+): 442.

Example 39a:8-(4-Amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of 4,6-dichloro-1,3,5-triazin-2-amine (1.6 g) inisopropanol (14 mL) was added 2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2, 3-dicarboxylate (1.28 g, 3.7 mmol) and Et₃N(7 mL). The solution was heated to reflux for 72 h, then cooled to RT,and concentrated in vacuo. Purification by normal phase chromatography(CH₂Cl₂/MeOH=50/1) afforded 2-benzyl 3-ethyl8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a colorless oil.

Step 2:

To a solution of 2-benzyl 3-ethyl8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(265 mg, 0.56 mmol) in isopropanol (3 mL) were addednaphthalen-2-ylmethanamine (105 mg, 0.67 mmol) and Et₃N (1.4 mL). Thereaction mixture was heated to reflux for 12 h, then cooled to RT, andconcentrated in vacuo. Purification by normal phase chromatography(CH₂Cl₂/MeOH) provided 2-benzyl 3-ethyl8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

Hydrolysis of 2-benzyl 3-ethyl8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateusing the LiOH general method provided8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as a white solid.

Step 4:

N-CBZ Deprotection was accomplished via Method B to provide the titlecompound as a white solid.

Using the generic scheme below, the following examples of Table 13a wereprepared as described above for8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 39a).

TABLE 13a

Ex. LCMS No. A—CH(R)—NH— CAS Name (MH+) 39a

8-(4-amino-6-((naphthalen-2-ylmethyl) amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 435 39b

8-(4-(([1,1′-biphenyl]-4-ylmethyl) amino)-6-amino-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5] decane-3-carboxylic acid 460 39c

8-(4-amino-6-((2-(piperazin-1-yl) benzyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 467 39d

8-(4-(([1,1′-biphenyl]-3-ylmethyl) amino)-6-amino-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 460 39e

8-(4-amino-6-(((R)-1-(naphthalen- 2-yl)ethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5] decane-3-carboxylic acid 448

TABLE 13b NMR Data for Compounds of Table 13a Ex. No. NMR 39a 1H NMR(400 MHz, DMSO-d6): δ ppm 1.5 (br.s. 4 H), 1.6-1.8 (m, 1H), 2.1-2.2 (m,1H), 3.0-3.1 (br.s. 3H), 3.5-3.8 (br.s. 5 H), 4.1 (t, J = 4.8 Hz, 1 H),4.5 (d, J = 5.5 Hz, 2 H), 6.0-6.3 (br.s. 2 H), 7.1-7.3 (m, 3H), 7.5-7.9(m, 4 H). 39b 1H NMR (400 MHz, MeOH-d4): δ ppm 1.54-1.79 (m, 4 H)2.02-2.19 (m, 1 H) 2.44-2.60 (m, 1 H) 3.74-3.92 (m, 2 H) 3.93-4.08 (m, 2H) 4.49-4.62 (m, 1 H) 4.63-4.71 (m, 2 H) 7.30-7.40 (m, 1 H) 7.40-7.51(m, 4 H) 7.55-7.68 (m, 4 H) 39c 1H NMR (400 MHz, MeOH-d4): δ ppm 1.66(br. s., 6 H) 1.86 (br. s., 4 H) 2.03-2.16 (m, 1 H) 2.40-2.54 (m, 1 H)3.06-3.22 (m, 4 H) 3.66-3.87 (m, 2 H) 3.87-4.02 (m, 2 H) 4.46-4.59 (m, 1H), 4.75 (s, 2 H) 7.12-7.27 (m, 1 H) 7.29-7.45 (m, 3 H) 39d 1H NMR (400MHz, MeOH-d4): δ ppm 1.29-1.79 (m, 4 H) 1.88-2.15 (m, 1 H) 2.25-2.54 (m,1 H) 3.22 (br. s., 2 H) 3.60-4.01 (m, 4 H) 4.35-4.54 (m, 1 H) 4.62 (s, 2H) 7.25-7.35 (m, 1 H) 7.36-7.46 (m, 3 H) 7.51 (d, J = 7.61 Hz, 1 H) 7.57(d, J = 8.59 Hz, 3 H) 39e 1H NMR (400 MHz, MeOH-d4): δ ppm 1.63 (d, J =6.83 Hz, 9 H) 3.01-3.21 (m, 1 H) 3.50-4.07 (m, 5 H) 4.32-4.65 (m, 1 H)5.14-5.33 (m, 1 H) 7.32-7.54 (m, 3 H) 7.81 (d, J = 5.08 Hz, 4 H)

Example 40:8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(380 mg, 1.3 mmol) in 10 mL of THF was added NaH (60 mg, 1.4 mmol) andthe reaction was stirred at RT for 30 min. After this time, 2-benzyl3-ethyl8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(product from Step 1, Example 39a) (570 mg, 1.2 mmol) was added and thereaction was heated to 50° C. for 12 h. After this time, the reactionwas cooled to RT, quenched with methanol and concentrated in vacuo.Normal phase silica gel chromatography (EtOAc/heptane) provided 2-benzyl3-ethyl8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

N-CBZ Deprotection was accomplished via Method B to provide ethyl8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Step 3: Hydrolysis of ethyl8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as a whitesolid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.55 (br. s., 4H) 1.98 (s, 1H)2.02-2.15 (m, 1H) 2.30 (dd, J=13.42, 9.27 Hz, 1H) 2.36 (s, 3H) 3.10 (d,J=11.71 Hz, 1H) 3.23-3.28 (m, 1H) 3.40-4.01 (m, 4H) 4.08 (dd, J=9.27,6.88 Hz, 1H) 6.39 (d, J=2.25 Hz, 1H) 7.36-7.63 (m, 3H) 7.76 (d, J=8.54Hz, 1H) 7.91 (d, J=2.10 Hz, 1H). LCMS (MH+): 567.

Example 41a:(S)-8-(2-Amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-chloropyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.6 mmol) and[2-(1-piperidinyl)phenyl]methanamine (CAS#: 72752-54-6) (105 mg, 0.8mmol) in i-PrOH (2 mL) was added diisopropylethyl amine (0.5 mL). Thereaction was heated to 120° C. for 2 h followed by heating to 140° C.for 1 h under microwave conditions, then cooled to RT and concentratedin vacuo. Purification by normal phase silica gel column (EtOAc/heptane)provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a whitesolid.

Step 2:

N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of (S)-ethyl8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as a whitesolid.

Using the generic scheme below, the following examples of Table 14a wereprepared as described above for(S)-8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 41a).

TABLE 14a

Ex. LCMS No. Ar CAS Name (MH+) 41a

(S)-8-(2-amino-6-((2-(piperidin-1- yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 446 41b

(S)-8-(2-amino-6-((2-phenxoy-6-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 558 41c

(3S)-8-(6-(((3S,5S)-adamantan-1-ylmethyl)amino)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 44141d

(3S)-8-(6-((1-((1R,3S,5S)-adamantan-1-yl)ethyl)amino)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 456

TABLE 14b NMR Data for Compounds of Table 14a Ex. No. NMR 41a ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.39-1.66 (m, 6 H) 1.67-1.85 (m, 4 H)1.95-2.11 (m, 1 H) 2.18-2.35 (m, 1 H) 2.69-2.95 (m, 4 H) 3.09 (s, 1 H)3.20 (s, 1 H) 3.35 (s, 4 H) 3.94-4.14 (m, 1 H) 4.43 (s, 2 H) 6.93-7.05(m, 1 H) 7.11 (s, 1 H) 7.14-7.24 (m, 1 H) 7.26-7.38 (m, 1 H) 41b ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.43-1.66 (m, 6 H) 1.67-1.85 (m, 4H) 1.94-2.09(m, 1 H) 2.18-2.34 (m, 1 H) 2.89 (d, J = 4.49 Hz, 4 H) 3.07 (s, 1 H)3.14-3.25 (m, 1 H) 3.32-3.63 (m, 4 H) 3.95-4.08 (m, 1 H) 4.46 (s, 2 H)6.49-6.58 (m, 1 H) 6.84-6.97 (m, 3 H) 7.03-7.09 (m, 1 H) 7.18 (s, 1 H)7.28 (d, J = 7.91 Hz, 2 H) 41c ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.00(br. s., 6 H) 0.03-0.26 (m, 10 H) 0.27-0.44 (m, 9 H) 0.48-0.58 (m, 1 H)0.68-0.85 (m, 1 H) 1.33 (s, 2 H) 1.50-1.64 (m, 1 H) 1.84-2.03 (m, 2 H)2.11 (br. s., 2 H) 2.42-2.62 (m, 1 H) 41d ¹H NMR (400 MHz, MeOH-d4): δppm 1.08 (d, J = 6.83 Hz, 3 H) 1.52-1.71 (m, 13 H) 1.73 (br. s., 3 H)1.93 (s, 2 H) 1.97 (br. s., 3 H) 2.04-2.19 (m, 1 H) 2.24-2.43 (m, 1 H)3.06-3.21 (m, 1 H) 3.22-3.28 (m, 1 H) 3.36-3.58 (m, 3 H) 3.59-3.75 (m, 2H) 4.02-4.20 (m, 1 H)

Example 42a:(S)-8-(2-amino-6-((R)-1-(3′-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made as described for(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 35) starting with (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.43 (h, J=8.5, 6.5 Hz, 4H), 1.80 (dd,J=13.3, 7.4 Hz, 1H), 2.12 (dd, J=13.2, 9.0 Hz, 1H), 2.48 (d, J=1.8 Hz,1H), 2.95 (d, J=11.7 Hz, 1H), 3.08 (d, J=11.7 Hz, 1H), 3.37 (d, J=16.1Hz, 1H), 3.48 (d, J=11.2 Hz, 3H), 3.79 (m, 2H), 5.57 (s, 1H), 6.62 (q,J=6.9 Hz, 1H), 7.27 (dd, J=5.8, 3.3 Hz, 1H), 7.51 (m, 7H). LCMS (MH+):563.

Example 42b:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made as described for(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 35) starting with (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, DMSO-d6): δ ppm 0.89 (m, 1H), 1.30 (d, J=16.3 Hz, 3H),1.60 (q, J=5.9 Hz, 4H), 2.05 (dd, J=13.4, 7.2 Hz, 1H), 2.32 (dd, J=13.4,9.1 Hz, 1H), 3.11 (d, J=11.7 Hz, 1H), 3.24 (d, J=11.7 Hz, 1H), 3.47(ddt, J=20.6, 13.4, 6.5 Hz, 2H), 3.64 (ddt, J=15.8, 10.8, 5.2 Hz, 2H),4.07 (dd, J=9.2, 7.1 Hz, 1H), 5.51 (s, 1H), 6.68 (q, J=6.9 Hz, 1H), 7.25(m, 4H), 7.48 (m, 3H), 7.71 (m, 1H). LCMS (MH+): 546.

Example 43:(S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(1.00 g, 3.44 mmol, Intermediate 3) in 1,4-dioxane (100 mL) was added3,5-dichloropyridazine (512 mg, 3.44 mmol) and Cs₂CO₃ (3.36 g, 10.3mmol). The reaction mixture was then heated at 100° C. for 182 h. Duringthis time, the reaction was charged with additional3,5-dichloropyridazine (2.56 g, 17.2 mmol) at t=86 h. Then the reactionmixture was cooled to RT, diluted with water, and extracted with EtOAc.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification on a 120 g Isco RediSep silicacartridge (EtOAc/heptane) provided3-chloro-5-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyridazineas a 3:2 mixture of(R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazineand(R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazinerespectively.

Step 2:

To a solution of the(R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine/(R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazinemixture from step 1 in 1,4-dioxane (19 mL) was added 2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (980 mg, 2.83 mmol), Cs₂CO₃(2.30 g, 7.07 mmol), Pd₂(dba)₃ (432 mg, 0.471 mmol), and rac-BINAP (587mg, 0.940 mmol), and the reaction mixture was heated to 60° C. for 60 h.Then the reaction mixture was cooled to RT, filtered through celite,washed with EtOAc, and the filtrate concentrated in vacuo. Purificationon a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

N-CBZ Deprotection was accomplished via Method B to provide(S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylicacid as a white solid.

Step 4:

Hydrolysis of(S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylicacid using the LiOH general method provided the title compound as anoff-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.66-1.80 (m, 4H), 2.11 (dd, J=13.45,7.05 Hz, 1H), 2.30-2.40 (m, 1H), 2.36 (s, 3H), 3.16 (d, J=11.81 Hz, 1H),3.25-3.35 (m, 1H), 3.37-3.65 (m, 4H), 4.03-4.19 (m, 1H), 6.39 (d, J=2.34Hz, 1H), 6.63 (d, J=2.39 Hz, 1H), 6.95 (q, J=6.39 Hz, 1H), 7.43-7.57 (m,2H), 7.76 (d, J=8.35 Hz, 1H), 8.22 (d, J=2.39 Hz, 1H), 8.63 (d, J=2.49Hz, 1H). LCMS (MH+): 551

Example 44:(S)-8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid and Example 45:(S)-8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of 2-chloro-4-nitropyridine (200 mg, 1.00 mmol) in1,4-dioxane (6 mL) was added(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(368 mg, 1.27 mmol), and Cs₂CO₃ (828 mg, 2.54 mmol). The reaction washeated to 80° C. for 12 h, then cooled to RT, diluted with water, andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column (EtOAc/heptane) provided(R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridineas an off-white solid.

Step 2:

To a solution of(R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridine(227 mg, 0.57 mmol) in 1,4-dioxane (5 mL) was added 2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (237 mg, 0.68 mmol), Cs₂CO₃(557 mg, 1.71 mmol), BINAP (142 mg, 0.23 mmol), and Pd₂(dba)₃. Thereaction was heated to 60° C. for 3 d, then cooled to RT, andconcentrated in vacuo. Purification by normal phase silica gel column(EtOAc/heptane) provided 2-benzyl 3-ethyl8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

Hydrolysis of 2-benzyl 3-ethyl8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateusing the LiOH general method provided2-((benzyloxy)carbonyl)-8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid.

Step 4:

N-CBZ Deprotection was accomplished via Method A followed by normalphase silica gel purification (EtOAc:heptane) providing both of thetitle compounds as white solids (120 mg and 75 mg for the des-chloroanalog).

8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.52-1.76 (m, 4H) 1.95-2.15 (m, 1H)2.23-2.37 (m, 1H) 2.39 (s, 3H) 2.87 (s, 1H) 3.05-3.16 (m, 1H) 3.19-3.27(m, 1H) 3.38-3.72 (m, 4H) 3.77-4.13 (m, 1H) 6.39 (d, J=2.44 Hz, 1H)6.44-6.52 (m, 1H) 6.79 (d, J=2.20 Hz, 1H) 6.83-6.97 (m, 1H) 7.43-7.51(m, 1H) 7.54 (d, J=2.05 Hz, 1H) 7.66 (d, J=8.74 Hz, 1H) 7.81-8.00 (m,2H). LCMS (MH+): 550.

8-(4-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.47-1.71 (m, 4H) 1.95-2.04 (m, 1H)2.21-2.31 (m, 1H) 2.39 (s, 3H) 2.73 (s, 1H) 3.02 (d, J=11.52 Hz, 1H)3.14-3.22 (m, 1H) 3.37-4.03 (m, 4H) 6.36 (d, J=2.34 Hz, 1H) 6.43-6.51(m, 1H) 6.72-6.85 (m, 2H) 7.30-7.51 (m, 3H) 7.52-7.61 (m, 1H) 7.67 (d,J=7.86 Hz, 1H) 7.81 (d, J=2.34 Hz, 1H) 7.86-7.91 (m, 1H). LCMS (MH+):516.

Example 46:8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of 2-benzyl 3-ethyl8-(4-chloro-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(by-product from Step 3, Example 30a) (250 mg, 0.347 mmol) in1,4-dioxane (9.0 mL) was added phenol (1.00 g, 10.6 mmol) and Cs₂CO₃(3.65 g, 11.2 mmol). The reaction was heated at 80° C. for 12 h, thencooled to RT diluted with water, and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. Purification on a 12 g Isco RediSep silica cartridge(EtOAc/heptane) provided 2-benzyl 3-ethyl8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 2:

N-CBZ Deprotection was accomplished via Method A to provide (ethyl8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of ethyl8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as anoff-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.36 (br. s., 4H), 1.90-1.99 (m, 1H),2.11-2.21 (m, 1H), 2.26 (s, 3H), 2.92-3.17 (m, 2H), 3.24-3.60 (m, 4H),3.96 (dd, J=9.13, 6.88 Hz, 1H), 5.44 (d, J=2.29 Hz, 1H), 6.27-6.33 (m,1H), 7.00 (d, J=8.00 Hz, 2H), 7.08-7.16 (m, 1H), 7.24-7.32 (m, 2H), 7.38(dd, J=8.44, 1.90 Hz, 1H), 7.44 (d, J=2.00 Hz, 1H), 7.54-7.62 (m, 1H),7.64 (d, J=8.49 Hz, 1H), 7.81 (d, J=2.25 Hz, 1H). LCMS (MH+): 642.

Example 47:(3S)-8-(2-Amino-6-(1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d) starting with1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.62 (q, J=5.7 Hz, 4H),2.06 (m, 1H), 2.33 (dd, J=13.5, 9.2 Hz, 1H), 3.13 (d, J=11.7 Hz, 1H),3.26 (d, J=11.7 Hz, 1H), 3.49 (m, 2H), 3.65 (dq, J=10.7, 5.4 Hz, 2H),4.09 (dd, J=9.2, 7.2 Hz, 1H), 5.56 (s, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.28(q, J=8.0 Hz, 1H), 7.69 (m, 2H). LCMS (MH+): 611.

Example 48:(S)-8-(2-Amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d) starting with1-(2,5-dibromophenyl)-2,2,2-trifluoroethanol.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (q, J=5.8, 5.2 Hz, 4H), 2.06 (dd,J=13.5, 7.2 Hz, 1H), 2.34 (dd, J=13.4, 9.2 Hz, 1H), 3.13 (d, J=11.7 Hz,1H), 3.26 (d, J=11.8 Hz, 1H), 3.50 (m, 2H), 3.66 (ddt, J=15.0, 10.7, 5.2Hz, 2H), 4.09 (dd, J=9.2, 7.2 Hz, 1H), 4.83 (s, 1H), 5.58 (s, 1H), 6.97(q, J=6.6 Hz, 1H), 7.47 (dd, J=8.6, 2.4 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H),7.69 (d, J=2.4 Hz, 1H). LCMS (MH+): 611.

Example 49:(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromo-5-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(660 mg, 0.95 mmol) in dioxane (12 mL) was added(3-(methylsulfonyl)phenyl)boronic acid (285 mg, 1.43 mmol), Pd₂(dppf)Cl₂(70 mg, 0.095 mmol) and Na₂CO₃ (6.0 mL, 2.0 M, aq). The reaction washeated to 90° C. for 2 h, then cooled to RT, concentrated in vacuo. Theresidue was taken up in CH₂Cl₂, washed with brine, and extracted withCH₂Cl₂. The combined organic layers were dried over Na₂SO₄. Purificationby normal phase silica gel column (EtOAc/heptane) provided(S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(4-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

To a solution of (S)-2-test-butyl 3-ethyl8-(2-amino-6-((R)-1-(4-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(500 mg, 0.65 mmol) in DMF (10 mL) was addedtributyl(prop-1-enyl)stannane (258 mg, 0.78 mmol), Pd(t-Bu₃P)₂ (33 mg,0.065 mmol), and CsF (217 mg, 1.43 mmol). The reaction was heated to130° C. in a sealed tube for 3 h, then cooled to RT. The reactionmixture was partitioned between water and CH₂Cl₂, and extracted. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by normal phase silicagel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(200 mg, 0.26 mmol) in EtOH (10 mL) was added 10% Pd/C (200 mg) and thereaction mixture was stirred under 1 atm H₂ for 12 h. The solids werefiltered and the filtrate was concentrated to afford (S)-2-tert-butyl3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid that is used directly without further purification.

Step 4:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH₂Cl₂ (4 mL) was added TFA (2.0 mL)dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, thenconcentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueousNaHCO₃ solution. The aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by normal phase silicagel column (CH₂Cl₂/MeOH) provided the title compound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 8.41 (m, 1H), 8.04 (d, J=7.8 Hz, 1H),7.79 (t, J=7.8 Hz, 1H), 7.73-7.71 (m, 1H), 7.53 (s, 1H), 7.33 (d, J=7.8Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 6.61 (q, J=6.7 Hz, 1H), 5.61 (s, 1H),4.10 (t, J=8.4 Hz, 1H), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 2H), 3.26 (m,1H), 3.21 (s, 3H), 3.16-3.13 (m, 1H), 2.66 (t, J=7.6 Hz, 2H), 2.38-2.32(m, 1H), 2.10-2.05 (m, 2H), 1.65-1.60 (m, 3H). LCMS (MH+): 649.

Example 50:(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for (S)-2-tert-butyl3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(Example 49) by omitting the olefin hydrogenation reaction of Step 3.

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 8.46-8.42 (m, 1H), 8.06-8.03 (m, 1H),7.82-7.71 (m, 2H), 7.64 (s, 1H), 7.45 (dd, J1=8.2 Hz, J2=33.2 Hz, 1H),7.25 (dd, J1=7.9 Hz, J2=23.9 Hz, 1H), 6.64-6.62 (m, 1H), 6.49-6.45 (m,1H), 6.39-5.86 (m, 1H), 5.62 (d, J=5.3 Hz, 1H), 4.12-4.08 (m, 1H),3.70-162 (m, 2H), 3.54-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.22-3.21 (m,3H), 3.16-3.13 (m, 1H), 2.37-2.31 (m, 1H), 2.10-2.05 (m, 1H), 1.91-1.87(m, 3H), 1.62 (m, 4H). LCMS (MH+): 647.

Example 51a:(S)-8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(660 mg, 0.95 mmol) in dioxane (12 mL) was added phenyl boronic acid(290 mg, 2.4 mmol), Pd₂(dppf)Cl₂ (70 mg, 0.095 mmol), and Na₂CO₃ (6.0mL, 2.0 M, aq). The reaction mixture was heated to 90° C. for 2 h, thencooled to RT, concentrated in vacuo, and extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, and dried over Na₂SO₄.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-2-tert-butyl 3-ethyl8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

To a solution of (S)-2-tert-butyl 3-ethyl8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(550 mg, 0.75 mmol) in CH₂Cl₂ (4 mL) was added TFA (2.0 mL) dropwise at0° C. The reaction mixture was stirred at RT for 2 h, and concentratedin vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCO₃solution. The aqueous layer was extracted with CH₂Cl₂. The organic layeris washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by normal phase silica gel column (CH₂Cl₂/MeOH)provided (S)-ethyl8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of (S)-ethyl8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as a whitesolid.

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 7.91 (s, 1H), 7.70 (dd, J1=6.08 Hz,J=1.88 Hz, 1H), 7.62 (m, 2H), 7.56-7.44 (m, 7H), 7.39-7.35 (m, 2H), 6.72(q, J=6.52 Hz, 1H), 5.48 (s, 1H), 4.18 (q, J=6.96 Hz, 2H), 3.67 (m, 1H),3.58 (m, 2H), 3.41 (m, 2H), 2.98 (d, J=10.96 Hz, 1H), 2.69 (d, J=11.24Hz, 1H), 2.12-2.06 (m, 1H), 1.83-1.78 (m, 1H), 1.52 (m, 4H). LCMS (MH+):604.5

Example 51b:(S)-8-(6-((R)-1-([1,1′:3′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described for(S)-8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 51a) starting with (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(product of Step 4, example 63ao).

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 1.32 (dd, J=15.5, 7.9 Hz, 1H), 1.70(dd, J=7.9, 4.3 Hz, 5H), 2.12 (m, 1H), 2.49 (ddd, J=12.3, 9.0, 2.6 Hz,1H), 3.25 (dd, J=11.9, 2.2 Hz, 1H), 3.60 (s, 9H), 4.48 (t, J=8.6 Hz,1H), 6.89 (q, J=7.8 Hz, 1H), 7.21 (d, J=7.6 Hz, 2H), 7.42 (m, 14H). LCMS(MH+): 604.

Example 52a:(S)-8-(2-Amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(product of Step 1, Example 34w) (273 mg, 0.34 mmol) in 1,4-dioxane (5mL) was added (3,4-dimethylphenyl)boronic acid (77 mg, 0.51 mmol), KHCO₃(341 mg, 3.40 mmol), and Pd(PCy₃)₂ (34 mg, 0.051 mmol). The reaction washeated to 100° C. for 44 h. The reaction was charged with additionalPd(PCy₃)₂ (68 mg, 0.10 mmol) at t=16 and 39 h. Then the reaction wascooled to RT and extracted with EtOAc. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. Purification ona 12 g Isco RediSep silica cartridge (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an white solid.

Step 2:

N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a whitesolid.

Step 3:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOHgeneral method provided the title compound as an off-white solid.

Using the generic scheme below, the following examples of Table 16a wereprepared as described above for(S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 52a).

TABLE 16a

Ex. LCMS No. Cy CAS Name (MH+) 52a

(S)-8-(2-amino-6-((R)- 1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylic acid 710 52b

(S)-8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-(quinolin-6-yl)-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylic acid 733

TABLE 16b NMR Data for Compounds of Table 16a Ex. No. NMR 52a ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.46-1.73 (m, 4 H) 2.07 (dd, J = 13.45, 7.15Hz, 1 H) 2.28 (s, 3 H) 2.30 (s, 3 H) 2.32-2.40 (m, 1 H) 3.14 (d, J =11.76 Hz, 1 H) 3.22 (s, 3 H) 3.27 (d, J = 11.76 Hz, 1 H) 3.40-3.77 (m, 4H) 4.09 (dd, J = 9.08, 7.27 Hz, 1 H) 5.62 (s, 1 H) 6.63 (q, J = 6.64 Hz,1 H) 7.18 (d, J = 7.96 Hz, 1 H) 7.35 (dd, J = 7.81, 1.81 Hz, 1 H) 7.40(s, 1 H) 7.47 (d, J = 1.85 Hz, 1 H) 7.63-7.72 (m, 1 H) 7.72-7.77 (m, 1H) 7.80-7.85 (m, 2 H) 8.07 (dt, J = 6.97, 1.96 Hz, 1 H) 8.48 (br. s., 1H) 52b ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (t, J = 5.54 Hz, 4 H) 1.92(dd, J = 13.13, 7.03 Hz, 1 H) 2.20 (dd, J = 13.15, 9.10 Hz, 1 H)2.81-3.17 (m, 2 H) 3.24 (s, 3 H) 3.38-3.74 (m, 4 H) 3.84 (dd, J = 8.96,7.05 Hz, 1 H) 5.64 (s, 1 H) 6.67 (q, J = 6.64 Hz, 1 H) 7.55 (dd, J =8.35, 4.34 Hz, 1 H) 7.67 (d, J = 1.61 Hz, 1 H) 7.78-7.92 (m, 4 H)8.04-8.15 (m, 3 H) 8.21 (s, 1 H) 8.41 (dd, J = 8.40, 1.56 Hz, 1 H) 8.54(br. s., 1 H) 8.84 (dd, J = 4.32, 1.68 Hz, 1 H)

Example 53:(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(600 mg, 0.89 mmol) in dioxane (12 mL) was added(3-(methylsulfonyl)phenyl)boronic acid (275 mg, 1.3 mmol), Pd₂(dppf)Cl₂(65 mg, 0.095 mmol), and Na₂CO₃ (6.0 mL, 2.0 M, aq). The reaction washeated to 90° C. for 2 h, then cooled to RT, and concentrated in vacuo.The residue was taken up in CH₂Cl₂, washed with brine, and dried overNa₂SO₄. Purification by normal phase silica gel column (EtOAc/heptane)provides (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 2:

To a solution (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(500 mg, 0.65 mmol) in DMF (10 mL) was addedtributyl(prop-1-enyl)stannane (258 mg, 0.78 mmol), Pd(t-Bu₃P)₂ (33 mg,0.065 mmol), and CsF (217 mg, 1.43 mmol). The reaction was heated to130° C. in a sealed tube for 3 h, then cooled to RT, and partitionedbetween water and CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylatein CH₂Cl₂ (4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reactionmixture was stirred at RT for 2 h, then concentrated in vacuo. The pHwas adjusted to 7-8 with a saturated aqueous NaHCO₃ solution. Theaqueous layer was extracted with CH₂Cl₂, washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column (CH₂Cl₂/MeOH) provided (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 4:

Hydrolysis of(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid using the LiOH general method provided the title compound as anoff-white solid.

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 8.40 (s, 1H), 8.02 (d, 1H, J=7.4 Hz),7.50 (m, 3H), 7.40 (m, 1H), 7.20 (m, 1H), 6.58 (m, 1H), 5.58 (m, 1H),4.09 (m, 1H), 3.55 (m, 2H), 3.48 (m, 2H), 3.21 (m, 4H), 3.10 (m, 1H),2.59 (m, 2H), 2.29 (m, 1H), 1.95 (m, 1H), 1.86 (m, 3H), 1.30 (m, 4H).LCMS (MH+): 646.

Example 54a:(S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product from Step 2, Example53) (200 mg, 0.26 mmol) in EtOH (10 mL) is added 10% Pd/C (200 mg), andthe reaction mixture was stirred under 1 atm H₂ for 12 h. The solidswere filtered and the filtrate was concentrated in vacuo to provide(S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid that is used directly without further purification.

Step 2:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH₂Cl₂ (4 mL) was added TFA (2.0 mL)dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, thenconcentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueousNaHCO₃ solution. The aqueous layer was extracted with CH₂Cl₂, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification by normal phase silica gel column (CH₂Cl₂/MeOH) provided(S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a white solid.

Step 3:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provides the title compound as anoff-white solid.

¹H NMR (400 MHz, CD₃OD-d4): δ ppm 8.40 (s, 1H), 8.02 (d, 1H, J=7.8 Hz),7.60 (m, 3H), 7.29 (m, 1H), 7.08 (s, 1H), 6.58 (m, 1H), 5.56 (s, 1H),4.00 (m, 1H), 3.55 (m, 2H), 3.48 (m, 2H), 3.31 (m, 4H), 3.30 (m, 1H),2.59 (m, 2H), 2.29 (m, 1H), 1.95 (m, 1H), 1.54 (m, 6H), 0.95 (m, 3H).LCMS (MH+): 649.

Example 54b:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (S)-ethyl8-(2-amino-6-((R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(350 mg, 0.56 mmol) in CH₂Cl₂ (20 mL) was added Boc₂O (436 mg, 2.0 mmol)and Et₃N (306 mg, 3.03 mmol) at 0° C. The reaction mixture was stirredat RT for 3 h, then concentrated in vacuo and purified on normal phasesilica gel (ethyl acetate/hexanes) to afford (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a yellow solid.

Step 2:

A solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(150 mg, 0.2 mmol), 4-isopropoxyphenyl boronic acid (44 mg, 0.25 mmol)and Pd(dppf)Cl₂ (15 mg, 0.02 mmol) in dioxane (3.0 mL)/aqueous Na₂CO₃solution (3.0 mL, 2.0 M, aq.) was stirred at 90° C. for 2 h. The aqueouslayer was extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification by normal phase silicagel column (EtOAc/Hex=10 to 50%) to (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(130 mg, 0.164 mmol) in CH₂Cl₂ (4 mL) was added TFA (1 mL), and thereaction mixture was stirred at 25° C. for 12 h. The mixture wasconcentrated, and neutralized to pH 7-8 with saturated aqueous NaHCO₃.The aqueous layer was extracted with CH₂Cl₂, washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to provide (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a light yellow solid that is used without further purification.

Step 4:

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateusing the LiOH general method provided the title compound as anoff-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (d, J=6.0 Hz, 6H), 1.58 (m, 4H),2.04 (dd, J=13.4, 7.2 Hz, 1H), 2.32 (dd, J=13.4, 9.2 Hz, 1H), 3.11 (d,J=11.7 Hz, 1H), 3.24 (d, J=11.7 Hz, 1H), 3.45 (ddd, J=21.2, 10.1, 6.4Hz, 2H), 3.60 (td, J=12.4, 11.2, 6.0 Hz, 2H), 4.08 (dd, J=9.1, 7.1 Hz,1H), 4.62 (p, J=6.1 Hz, 1H), 6.67 (q, J=6.8 Hz, 1H), 6.95 (m, 2H), 7.54(m, 9H), 7.72 (d, J=8.3 Hz, 1H). LCMS (MH+): 663.

Example 54c:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-propoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 54b) by substituting 4-propoxyphenyl boronic acid for4-isopropoxyphenyl boronic acid in Step 2.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.04 (t, J=7.4 Hz, 3H), 1.57 (m, 4H),1.80 (h, J=6.7 Hz, 2H), 1.99 (dd, J=13.3, 7.3 Hz, 1H), 2.27 (dd, J=13.3,9.1 Hz, 1H), 3.02 (d, J=11.6 Hz, 1H), 3.18 (d, J=11.5 Hz, 1H), 3.30 (d,J=3.2 Hz, 1H), 3.45 (q, J=15.9, 11.4 Hz, 2H), 3.60 (s, 2H), 3.97 (dt,J=13.1, 7.3 Hz, 3H), 4.88 (m, 1H), 5.47 (s, 1H), 6.66 (q, J=6.9 Hz, 1H),6.97 (d, J=8.3 Hz, 2H), 7.54 (m, 9H), 7.72 (m, 1H). LCMS (MH+): 662.

Example 54d:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (5 g, 21.3 mmol)in anhydrous methanol (100 mL) was added concentrated sulfuric acid (0.5mL). The resulting solution was stirred for 18 h at reflux. Uponcooling, the mixture was concentrated under reduced pressure, dissolvedin CH₂Cl₂ and washed with NaHCO₃ solution and brine. The organic phasewas dried over sodium sulfate and concentrated to afford methyl2-chloro-4-(methylsulfonyl)benzoate as a white solid.

Step 2:

To a mixture of methyl 2-chloro-4-(methylsulfonyl)benzoate (2.2 g, 8.9mmol), PhB(OH)₂ (1.31 g, 10.8 mmol), DME (12 mL), and 2M Na₂CO₃ (6 mL)was added Pd(PPh₃)₄ (515 mg). The mixture was heated for 20 min at 160°C. in a microwave reactor, and then extracted with EtOAc, dried oversodium sulfate and concentrated in vacuo. Purification on normal phasesilica gel (hexane/EtOAc) provided methyl5-(methylsulfonyl)-[1,1′-biphenyl]-2-carboxylate as a white solid.

Step 3:

To a solution of CaCl₂ (1.52 g, 13.78 mmol) in EtOH (50 mL) at RT wasadded methyl 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carboxylate (2 g, 6.9mmol) in THF (50 mL) followed by the addition of NaBH₄ (1.0 g, 27.6mmol). The reaction was stirred at RT for 24 h, then concentrated invacuo and extracted with ethyl acetate, 5% HCl, and brine. Purificationon normal phase silica gel provided(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methanol as a white solid.

Step 4:

To a solution of (5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methanol (1 g,3.8 mmol) in CH₂Cl₂ (50 mL) was added Dess-Martin periodinane (2.4 g,5.71 mmol). The reaction was stirred for 2 h at RT, then concentrated invacuo and purified directly on normal phase silica gel to provide5-(methylsulfonyl)-[1,1′-biphenyl]-2-carbaldehyde as a white solid.

Step 5:

To a solution of 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carbaldehyde (1 g,3.8 mmol) was added TMS-CF₃ (1.0 g, 7.7 mmol) in THF (10 mL). Thereaction was cooled to 0° C. to and TBAF (0.57 mL, 0.57 mmol) was addeddropwise. The reaction mixture was stirred for 2 h, then 3 N HCl (2 mL)was added to the mixture and the reaction mixture was stirred for anadditional 30 min. The mixture was extracted with ethyl acetate, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification on normal phase silica gel provided2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol as awhite solid.

Step 6:

To a mixture of2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol (720mg, 2.2 mmol)) in CH₂Cl₂ (50 mL) was added Dess-Martin periodinane (1.1g, 2.6 mmol). The reaction was stirred for 2 h at RT, then concentratedin vacuo and purified directly on normal phase silica gel to provide2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanone as awhite solid.

Step 7:

Chiral reduction of2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanoneusing the Iridium complex-catalyzed hydrogenation as described forIntermediate 1,(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol,provided(R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanolas a white solid.

Steps 8-11:

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 10d), Steps 1-4.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.63 (q, J=5.7, 4.9 Hz, 4H), 2.10 (m,1H), 2.36 (dd, J=13.5, 9.2 Hz, 1H), 3.23 (d, J=31.0 Hz, 5H), 3.50 (dddd,J=18.0, 13.4, 9.5, 5.1 Hz, 2H), 3.66 (ddt, J=15.9, 10.6, 4.6 Hz, 2H),4.16 (dd, J=9.2, 7.2 Hz, 1H), 6.78 (q, J=6.7 Hz, 1H), 7.57 (m, 5H), 7.86(d, J=1.9 Hz, 1H), 8.01 (m, 2H), 8.17 (s, 1H). LCMS (MH+): 607.

Example 54e:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-fluoro-4-propoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid inStep 2 with (3-fluoro-4-propoxyphenyl)boronic acid (CAS#192376-68-4).

¹H NMR (400 MHz, MeOH-d4): δ ppm 0.86 (m, 1H), 1.05 (t, J=7.4 Hz, 3H),1.26 (s, 1H), 1.59 (s, 4H), 1.83 (h, J=7.1 Hz, 2H), 2.06 (dd, J=13.4,7.2 Hz, 1H), 2.33 (m, 1H), 3.10 (d, J=11.9 Hz, 1H), 3.23 (d, J=12.0 Hz,1H), 3.43 (s, 2H), 3.60 (s, 2H), 4.02 (t, J=6.5 Hz, 2H), 4.12 (s, 1H),6.62 (d, J=6.8 Hz, 1H), 7.09 (t, J=8.7 Hz, 1H), 7.34 (s, 1H), 7.43 (m,4H), 7.50 (s, 3H), 7.60 (m, 1H), 7.76 (m, 2H). LCMS (MH+): 681.

Example 54f:(S)-8-(2-amino-6-((R)-1-(3,4-dimethyl-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid inStep 2 with 3,4-dimethylphenyl boronic acid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (s, 4H), 2.06 (dd, J=13.5, 7.6 Hz,1H), 2.29 (d, J=9.7 Hz, 5H), 2.37 (m, 1H), 3.17 (d, J=11.8 Hz, 1H), 3.26(d, J=11.7 Hz, 1H), 3.63 (d, J=14.2 Hz, 2H), 4.27 (t, J=8.3 Hz, 1H),6.66 (q, J=6.8 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.36 (m, 2H), 7.49 (m,5H), 7.64 (dd, J=8.2, 2.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H). LCMS (MH+):633.

Example 54g:(S)-8-(6-((R)-1-([1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 54b) by substituting phenyl boronic acid for4-isopropoxyphenyl boronic acid in Step 2.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (s, 4H), 2.06 (dd, J=13.5, 7.7 Hz,1H), 2.38 (dd, J=13.5, 9.1 Hz, 1H), 3.16 (d, J=11.8 Hz, 1H), 3.26 (d,J=11.8 Hz, 1H), 3.47 (s, 2H), 3.62 (s, 2H), 4.26 (t, J=8.4 Hz, 1H), 6.68(q, J=6.9 Hz, 1H), 7.35 (m, 1H), 7.47 (m, 4H), 7.53 (s, 3H), 7.66 (m,3H), 7.77 (d, J=8.2 Hz, 1H). LCMS (MH+): 604.

Example 54h:(R)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34c) by using (R)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J=5.5 Hz, 4H), 2.03 (dd,J=13.4, 7.1 Hz, 1H), 2.31 (dd, J=13.4, 9.2 Hz, 1H), 3.09 (d, J=11.8 Hz,1H), 3.23 (d, J=11.6 Hz, 1H), 3.46 (dt, J=15.3, 8.2 Hz, 2H), 3.62 (s,2H), 4.06 (dd, J=9.1, 7.1 Hz, 1H), 5.49 (s, 1H), 6.64 (q, J=6.9 Hz, 1H),7.28 (d, J=2.2 Hz, 1H), 7.46 (m, 5H), 7.53 (s, 1H), 7.67 (d, J=8.5 Hz,1H). LCMS (MH+): 562.

Example 54i:(R)-8-(2-amino-6-((S)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34c) by using (R)-2-benzyl 3-ethyl8-(2-amino-6-((S)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J=8.5 Hz, 1H), 7.59-7.44 (m,4H), 7.47-7.40 (m, 2H), 7.32 (d, J=2.2 Hz, 1H), 6.61 (q, J=6.5 Hz, 1H),4.51 (t, J=8.7 Hz, 1H), 3.72-3.59 (m, 1H), 3.56 (s, 1H), 3.28 (s, 1H),2.49 (dd, J=13.6, 8.9 Hz, 1H), 2.10 (dd, J=13.6, 8.4 Hz, 1H), 1.71 (dt,J=16.0, 6.6 Hz, 4H), 1.28 (s, 0H). LCMS (MH+): 562.

Example 54j:(S)-8-(2-amino-6-((S)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34c) by using (S)-2-benzyl 3-ethyl8-(2-amino-6-((S)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J=8.5 Hz, 1H), 7.61-7.42 (m,6H), 7.32 (d, J=2.3 Hz, 1H), 6.66 (q, J=6.7 Hz, 1H), 4.25 (dd, J=9.0,7.6 Hz, 1H), 3.72-3.60 (m, 1H), 3.29 (d, J=11.7 Hz, 1H), 3.18 (d, J=11.8Hz, 1H), 2.40 (dd, J=13.5, 9.2 Hz, 1H), 2.09 (dd, J=13.5, 7.6 Hz, 1H),1.64 (s, 2H). LCMS (MH+): 562.

Example 54k:(S)-8-(2-amino-6-((S)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 1m) by using (S)-2-benzyl 3-ethyl8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.58 (s, 6H), 2.04 (dd, J=13.4, 7.2 Hz,1H), 2.30 (d, J=11.1 Hz, 9H), 2.40 (s, 3H), 3.10 (d, J=11.8 Hz, 1H),3.23 (d, J=11.7 Hz, 1H), 3.48 (s, 2H), 3.66 (d, J=15.7 Hz, 3H), 4.08 (t,J=8.2 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.77 (q, J=6.5 Hz, 1H), 7.20 (d,J=7.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.60 (d,J=1.8 Hz, 1H), 7.73 (m, 2H), 7.97 (d, J=2.4 Hz, 1H). LCMS (MH+): 635.

Example 54l:(R)-8-(2-amino-6-((S)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for(R)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 1m) by using (R)-2-benzyl 3-ethyl8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (d, J=2.3 Hz, 0H), 7.79-7.69 (m,0H), 7.61 (d, J=1.6 Hz, 0H), 7.45 (s, 0H), 7.42-7.35 (m, 0H), 7.21 (d,J=7.9 Hz, 0H), 6.77 (q, J=6.5 Hz, 0H), 6.41 (d, J=2.3 Hz, 0H), 4.10 (t,J=8.2 Hz, 0H), 3.68 (dd, J=13.9, 6.3 Hz, 0H), 3.58-3.43 (m, 0H), 3.24(d, J=11.7 Hz, 0H), 3.11 (d, J=11.8 Hz, 0H), 2.42-2.27 (m, 1H), 2.05(dd, J=13.5, 7.2 Hz, 0H), 1.59 (d, J=11.4 Hz, 0H), 1.59 (s, 0H). LCMS(MH+): 635.

Example 54m:(R)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was prepared as described above for (R)-2-benzyl3-ethyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(Example 1m) by using (R)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (d, J=2.4 Hz, 1H), 7.79-7.68 (m,2H), 7.60 (d, J=1.7 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.20(d, J=7.8 Hz, 1H), 6.76 (q, J=6.7 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 5.75(s, 1H), 3.98 (t, J=8.1 Hz, 1H), 3.64 (d, J=15.5 Hz, 3H), 3.47 (s, 2H),3.33-3.27 (m, 6H), 3.17 (d, J=11.6 Hz, 1H), 3.01 (d, J=11.6 Hz, 1H),2.39 (s, 3H), 2.34-2.18 (m, 8H), 1.99 (dd, J=13.4, 7.1 Hz, 1H), 1.56 (s,5H). LCMS (MH+): 635.

Example 55an:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg,0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidin-2-amine(120 mg g, 0.71 mmol) and Cs₂CO₃ (290 mg, 0.88 mmol), and the reactionmixture was heated to 80° C. for 30 h. Then the reaction was cooled toRT. EtOAc was added and the organic layer was washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification by normalphase silica gel column (EtOAc/heptane) provided(R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amineas a colorless oil.

Step 2:

To a solution of(R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine(19 mg, 0.50 mmol) in dioxane (25 ml) was added (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (175 mg, 0.50 mmol) andsodium bicarbonate (210 mg, 0.25 mmol), and the reaction mixture washeated to 100° C. for 48 h. Then the reaction mixture was cooled to RT,and extracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification by normal phase silica gel column (EtOAc/heptane) provided(S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas white solid.

Step 3:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(190 mg, 0.27 mmol) was added NaOH (100 mg, 0.26 mmol) in 15 mLTHF/EtOH/H₂O (2/1/2.5), and the reaction was stirred for 12 h at RT.Then, the reaction mixture was concentrated in vacuo to remove most ofthe organic solvents, and the pH was adjusted to 6 with 1 N HCl. EtOAcwas added, and the organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to provide(S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as a white solid which was used without further purification.

Step 4:

To a solution of(S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (80 mg, 0.12 mmol) in dioxane (1 mL)/Na₂CO₃ (1.0 mL, 2 M, aq) wereadded (3-methoxyphenyl)boronic acid (22 mg, 0.14 mmol) and Pd(dppf)₂ (8mg, 0.01 mmol). The reaction flask was degassed and refilled with argonvia balloon 3 times, and the reaction mixture was refluxed for 4 h. Thenthe reaction was cooled to RT, concentrated in vacuo, and extracted withEtOAc. The combined organic layers were are washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification byreverse phase silica gel column (H₂O/NH₄OH/MeOH) provided(S)-8-(2-amino-6-((S)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as a white solid.

Step 5:

N-CBZ Deprotection was accomplished via Method A to provide the titlecompound as an off-white solid isolated as the zwitterionic form.

Using the generic scheme below, the following examples of Table 17a wereprepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 55an) using the appropriate boronic acid or boronate Insome cases, the Cy coupling reaction was performed prior to ethyl esterand N-CBz removal (see alternative Steps 3a and 4a) as noted in thescheme. In the cases of example 55al and 55am, racemic1-(4-bromophenyl)-2,2,2-trifluoroethanol was used as opposed to(R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol for all other examples.

TABLE 17a

Ex. LCMS No. Cy CAS Name (MH+) 55a

(S)-8-(6-((R)-1-([1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 529 55b

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-1H-indazol-5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 583 55c

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-1H-benzo[d]imidazol-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 583 55d

(S)-8-(6-((R)-1-(4-(1H-benzo[d]imidazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid 56955e

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 55f

(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 586 55g

(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isoxazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 570 55h

(S)-8-(6-((R)-1-(4-(1H-indazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 569 55i

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1- methyl-1H-indazol-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 583 55j

(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]isothiazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 586 55k

(S)-8-(2-amino-6-((R)-1-(4-(benzo[d]thiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 586 55l

(S)-8-(6-((R)-1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid 57055m

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(naphthalen-2-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 579 55n

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-2,8-diazaspiro[4.5]decane-3-carboxylic acid 573 55o

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-5′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-2,8-diazaspiro[4.5]decane-3-carboxylic acid 573 55p

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5′-methoxy-2′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 573 55q

(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethoxy-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 589 55r

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 656 55s

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-oxo-1,3-dihydroisobenzofuran-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 585 55t

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-1,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 596 55u

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-2-oxo-1,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 610 55v

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 598 55w

(S)-8-(6-((R)-1-(4-(1H-indazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 569 55x

(S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H- indazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylicacid 597 55y

(S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H- indol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 596 55z

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid627 55aa

(S)-8-(2-amino-6-((R)-1-(3′-cyano-5′-methoxy-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 584 55ab

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 586 55ac

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-methyl-1H-indol-5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid  1 55ad

(S)-8-(6-((R)-1-(3′-acetoxy-4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 645 55ae

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxo-2H-chromen-7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 596 55af

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 560 55ag

(S)-8-(2-amino-6-((R)-1-(4′-carboxy-3′-hydroxy-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 588 55ah

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methoxyquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 610 55ai

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2- (methylthio)quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 626 55aj

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylicacid 612 55ak

(3S)-8-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluoro-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 547 55al

(3S)-8-(2-amino-6-(2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 559 55am

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 547 55an

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 559 55ao

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-5′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 55ap

(S)-8-(2-amino-6-((R)-1-(3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 565 55aq

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 559 55ar

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 559 55as

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 597 55at

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(trifluoromethoxy)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 613 55au

(S)-8-(2-amino-6-((R)-1-(3′-ethoxy-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 573 55av

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-isopropoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 587 55aw

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(pyridin-3-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 530 55ax

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(pyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 530 55ay

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(pyrimidin-5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 531 55az

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3- methyl-1H-indazol-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylicacid 583 55ba

(S)-8-(2-amino-6-((R)-1-(4-(1,3-dimethyl-1H- indazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylicacid 597 55bb

S)-8-(2-amino-6-((R)-1-(4-(2,3-dimethyl-2H- indazol-6-yl)phenyl)-2,2,2-trifuoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylicacid 597 55bc

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 598 55bd

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 580 55be

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(isoquinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 580 55bf

(S)-8-(2-amino-6-((R)-1-(4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 586 55bg

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 580 55bh

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 580 55bi

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 581 55bj

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylicacid 612 55bk

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(quinazolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 581 55bl

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-fluoro-2′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 55bm

(S)-8-(2-amino-6-((R)-2,2,2-trifuoro-1-(2′-fluoro-3′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 55bn

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 55bo

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(6-methylpyridin-3-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 544 55bp

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 626 55bq

(S)-8-(2-amino-6-((R)-1-(3′-carboxy-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 573 55br

(S)-8-(2-amino-6-((R)-1-(4′-carboxy-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 573 55bs

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-propyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 571 55bt

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 559 55bu

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′-(hydroxymethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 559 55bv

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 587 55bw

(S)-8-(2-amino-6-((R)-1-(4′-(dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylicacid 600 55bx

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(piperidine-1-carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 640 55by

(S)-8-(2-amino-6-((R)-1-(2′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 586 55bz

(S)-8-(2-amino-6-((R)-1-(4′-ethyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 557 55ca

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-hydroxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 545 55cb

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-hydroxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 545 55cc

(S)-8-(2-amino-6-((R)-1-(2′,4′-dimethoxy-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 589 55cd

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 597 55ce

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 597 55cf

(S)-8-(2-amino-6-((R)-1-(2′,6′-difluoro-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 565 55cg

(S)-8-(2-amino-6-((R)-1-(2′,6′-dimethyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 557 55ch

(S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 557 55ci

(S)-8-(2-amino-6-((R)-1-(4′-(tert-butyl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 585 55cj

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 571 55ck

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-isopropyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 571 55cl

(S)-8-(2-amino-6-((R)-1-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 597 55cm

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 613 55cn

(S)-8-(2-amino-6-((R)-1-(2′,3′-dimethyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 557 55co

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 583 55cp

(S)-8-(2-amino-6-((R)-1-(4′-chloro-2′-methyl-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 55cq

(S)-8-(2-amino-6-((R)-1-(3′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 557 55cr

(S)-8-(2-amino-6-((R)-1-(3′,4′-difluoro-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 565 55cs

(S)-8-(2-amino-6-((R)-1-(2′,5″-dimethyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 557 55ct

(S)-8-(2-amino-6-((R)-1-(4′-butyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 585 55cu

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-methyl-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 561 55cv

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 607 55cw

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-methyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 543 55cx

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 543 55cy

(S)-8-(2-amino-6-((R)-1-(4′-chloro-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 563 55cz

(S)-8-(2-amino-6-((R)-1-(4-(benzofuran-3-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 569 55da

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(5′-fluoro-2′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 577 55db

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(2-oxochroman-7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 599 55dc

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 597 55dd

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 587 55de

(S)-8-(2-amino-6-((R)-1-(4′-(diethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid 628 55df

(S)-8-(2-amino-6-((R)-1-(4′-carbamoyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 572 55dg

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(methylcarbamoyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 585 55dh

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-((2-morpholinoethyl)carbamoyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid685 55di

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 606 55dj

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-sulfamoyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 607 55dk

(S)-8-(2-amino-6-((R)-1-(4′-(dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylicacid 600 55dl

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 641 55dm

(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-propoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 605 55dn

(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-3′-fluoro-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 591 55do

(S)-8-(2-amino-6-((R)-1-(4′-ethoxy-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 573 55dp

(S)-8-(2-amino-6-((R)-1-(4-(cinnolin-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 580 55dq

(S)-8-(2-amino-6-((R)-1-(4-(chroman-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid 584

TABLE 17b NMR Data for Compounds of Table 17a Ex. No. NMR 55a ¹H NMR(400 MHz, MeOH-d4): δ ppm 7.66-7.58 (m, 6H), 7.45-7.41 (m, 2H),7.36-7.32 (m, 1H), 6.64 (q, J = 6.8 Hz, 1H), 5.56 (s, 1H), 4.00 (m, 1H),3.67-3.60 (m, 2H), 3.52-3.44 (m, 2H), 3.20-3.02 (m, 2H), 2.31-2.25 (m,1H), 2.01 (m, 1H), 1.58 (s, 4H) 55b ¹H NMR (400 MHz, MeOH-d4): δ ppm8.02 (s, 1 H), 7.92 (s, 1 H), 7.67-7.65 (m, 3 H), 7.61-7.55 (m, 4H),6.60 (m, 1 H), 5.47 (s, 1 H), 3.97 (s, 4 H), 3.53 (m, 2 H), 3.35 (m, 2H), 3.15-3.12 (m, 1 H), 3.13-3.00 (m, 1 H), 2.21 (m, 1 H), 1.95 (m, 1H),1.50 (m, 4H) 55c ¹H NMR (400 MHz, MeOH-d4): δ ppm 8.16 (s, 1 H), 7.89(s, 1 H), 7.71-7.69 (d, 2 H), 7.63-7.60 (m, 4 H), 6.67-6.66 (q, 1 H),5.52 (s, 1 H), 4.00 (m, 1 H), 3.87 (s, 3 H), 3.62 (m, 2 H), 3.44 (m, 2H), 3.12 (d, 1 H), 3.06 (d, 1 H), 2.23 (m, 1 H), 1.99 (m, 1 H), 1.54 (m,4 H), 1.23 (m, 3 H). 55d ¹H NMR (400 MHz, MeOH-d4): δ ppm 8.56 (s, 1H),7.90 (s, 1H), 7.76-7.61 (m, 6H), 6.66 (q, J = 6.6 Hz, 1H), 5.59 (s, 1H),4.17-4.13 (m, 1H), 3.69-3.57 (m, 2H), 3.52-3.43 (m, 2H), 3.27-3.24 (m,1H), 3.16-3.13 (m, 1H), 2.37-2.31 (m, 1H), 2.09-2.04 (m, 5H), 1.61 (m,4H) 55e ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.62-7.56 (m, 4 H), 7.40 (m, 2H), 7.15 (m, 1 H), 6.61 (m, 1 H), 5.56 (m, 1 H), 4.07 (m, 1 H), 3.90 (s,3 H), 3.63 (m, 2 H), 3.48 (m, 2 H), 3.25 (m, 1 H), 3.13 (m, 1 H), 2.30(m, 1 H), 2.04 (m, 1 H), 1.60 (s, 4 H) 55f ¹H NMR (400 MHz, DMSO-d6): δppm 9.09 (s, 1 H), 8.45 (s, 1 H), 8.26 (m, 1 H), 7.83-7.77 (m, 3 H),7.64 (m, 2 H), 6.73 (m, 1H), 6.06 (s, 1H), 5.57 (s.1H), 3.45 (m, 4H),2.99 (m, 2 H), 2.10 (m, 1 H), 1.79 (m, 1 H), 1.42 (m, 4 H). 55g ¹H NMR(400 MHz, MeOH-d4): δ ppm 7.66-7.56 (m, 6H), 7.19-7.17 (m, 2H), 6.66 (q,J = 6.7 Hz, 1H), 5.56-5.55 (m, 1H), 4.08 (m, 1H), 3.64-3.59 (m, 2H),3.53-3.43 (m, 2H), 3.23-3.13 (m, 1H), 2.98-2.92 (m, 1H), 2.35-2.19 (m,1H), 2.08-2.03 (m, 1H), 1.59 (m, 4H). 55h ¹H NMR (400 MHz, MeOH-d4): δppm 8.06 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 7.7 Hz, 3H),7.62 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, 1H), 6.67 (q, J = 7.4 Hz,1H), 5.58 (s, 1H), 4.08 (m, 1H), 3.69-3.61 (m, 2H), 3.52-3.43 (m, 2H),3.23-3.10 (m, 2H), 2.35-2.30 (m, 1H), 2.08-2.03 (m, 1H), 1.60 (s, 4H).55i ¹H NMR (400 MHz, DMSO-d6): δ ppm 8.03 (s, 1 H), 7.83-7.82 (d, 2 H, J= 4.5 Hz), 7.81-7.79 (d, 2 H, J = 7.6 Hz), 7.62-7.60 (d, 2 H, J = 7.6Hz), 7.43-7.41 (d, 2 H, J = 8.6 Hz), 6.71-6.70 (q, 1 H, J = 6.8 Hz),5.55 (s, 1 H), 4.02 (s, 3 H), 3.71 (m, 1 H), 3.55-.344 (m, 4 H), 2.85(m, 1 H), 2.12 (m, 1 H), 1.71 (m, 1 H), 1.40 (m, 4 H). 55j ¹H NMR (400MHz, MeOH-d4): δ ppm 8.96 (s, 1 H), 8.33 (s, 1 H), 8.09-8.07 (d, 1 H, J= 8.8 Hz), 7.81-7.79 (dd, 1 H, J = 8.0 Hz), 7.71-7.69 (d, 2 H, J = 8.0Hz), 7.60-7.58 (d, 2 H, J = 8.0 Hz), 6.63-6.58 (q, 1 H), 5.51 (s.1H),4.00-3.96 (m, 1 H), 3.57 (m, 2 H), 3.40 (m, 2 H), 3.17-3.14 (d, 1 H, J =11.7 Hz), 3.13-3.00 (d, 1 H, J = 11.7 Hz), 2.23-2.21 (m, 1 H), 1.99-1.94(m, 1 H), 1.53 (m, 5 H). 55k ¹H NMR (400 MHz, MeOH-d4): δ ppm 9.26 (S, 1H), 8.33 (s, 1 H), 8.13-8.11 (d, 1 H, J = 8.5 Hz), 7.84-7.82 (dd, 1 H, J= 8.5 Hz), 7.76-7.74 (d, 2 H, J = 8.3 Hz), 7.65-7.63 (d, 2 H, J = 8.3Hz), 6.67-6.65 (q, 1 H, J = 7.2 Hz), 4.15-4.11 (m, 1 H), 3.53 (m, 2 H),3.49 (m, 2 H), 3.27-3.24 (d, 1 H, J = 11.7 Hz), 3.15-3.12 (d, 1 H, J =11.7 Hz), 3.33-2.31 (m, 1 H), 2.07-2.03 (m, 1 H), 1.61 (m, 5 H). 55l¹H-NMR (400 MHz, MeOH-d4): δ ppm 9.08 9 (s, 1H), 8.44 (s, 1H), 8.02-8.03(m, 1H), 7.83-7.86 (m, 2H), 7.66-7.75 (m, 2H), 6.66-6.69 (m, 1H), 5.50(s, 1H), 4.07-4.07 (m, 1H), 3.64-3.66 (m, 2H), 3.44-3.48 (m, 2H),3.19-3.24 (m, 1H), 3.16-3.46 (m, 1H), 2.29-2.55 (m, 1H), 2.03-2.08 (m,1H), 1.60-1.61 (m, 4H) 55m ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.19 (s,1H), 7.84-7.97 (m, 6H), 7.63-7.82 (m, 2H), 7.50-7.61 (m, 2H), 6.70-6.76(m, 1H), 5.58 (s, 1H), 3.38-3.47 (S, 1H), 3.00-3.00 (m, 1H), 2.91-2.94(m, 1H), 2.06-2.13 (m, 1H), 1.74-1.78 (m, 1H), 1.37-1.44 (m, 4H) 55n¹H-NMR (400 MHz, MeOH-d4): δ ppm 7.63-7.65 (m, 2H), 7.56-7.58 (m, 2H),7.15-7.20 (m, 1H), 7.07-7.09 (m, 2H), 6.60-6.65 (m, 1H), 4.11-4.16 (m,1H), 3.87 (s, 3H), 3.48-3.66 (m, 4H), 3.23-3.26 (m, 1H), 3.11-3.16 (m,1H), 2.31-3.41 (m, 1H), 2.20 (s, 3H), 2.02-2.10 (m, 1H), 1.59-1.61 (m,4H), 1.27-1.31 (m, 1H) 55o ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.62-7.56(m, 4H), 7.00 (s, 1H), 6.93 (s, 1H), 6.74 (s, 1H), 6.64 (q, 1H, J =8.0), 5.56 (d, 1H, J = 4.0), 4.08-4.04 (m, 1H), 3.80 (s, 3H), 3.63 (s,2H), 3.47 (s, 2H) 3.23 (d, 1H, J = 16.0), 3.10 (d, 1H, J = 12.0 Hz),2.36 (s, 3H), 2.04 (s, 1H), 1.59 (s, 1H), 1.28 (s, 1H) 55p ¹H NMR (400MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 1.30 (d, J = 15.5 Hz, 3H), 1.62 (d, J= 5.7 Hz, 5H), 2.06 (m, 1H), 2.14 (s, 3H), 2.33 (dd, J = 13.5, 9.2 Hz,1H), 3.13 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 11.3 Hz, 1H), 3.51 (dt, J =20.9, 6.7 Hz, 2H), 3.66 (d, J = 13.3 Hz, 2H), 3.76 (s, 3H), 4.09 (t, J =8.2 Hz, 1H), 5.57 (s, 1H), 6.69 (m, 2H), 6.81 (dd, J = 8.4, 2.8 Hz, 1H),7.15 (d, J = 8.4 Hz, 1H), 7.35 (m, 2H), 7.57 (d, J = 7.9 Hz, 2H) 55q ¹HNMR (400 MHz, MeOH-d4): δ ppm 7.62 (d, 2H, J = 8.0), 7.56 (d, 2H, J =8.0), 7.18 (m, 2H), 7.02 (d, 1H, J = 8.0), 6.62 (q, 1H, J = 8.0), 5.55(s, 1H), 4.01-3.97 (m, 1H), 3.31-3.23 (m, 1H), 3.89 (s, 3H), 3.86 (s,3H), 3.67-3.60 (m, 2H), 3.49-3.43 (m, 2H) 3.19 (d, 1H, J = 12.0), 3.02(d, 1H, J = 12.0 Hz), 2.27 (dd, 1H, J = 12.0, 8.0), 2.00 (dd, 1H, J =14.0, 4.0), 1.58 (s, 1H), 1.28 (s, 1H) 55r ¹H NMR (400 MHz, MeOH-d4): δppm 7.70-7.61 (m, 4H), 7.28 (m, 3H), 6.67 (q, J = 7.6 Hz, 1H), 5.56 (s,1H), 4.08 (m, 1H), 3.91 (s, 3H), 3.63-3.46 (m, 8H), 3.13 (m, 1H),2.35-2.29 (m, 1H), 2.01-1.99 (m, 1H), 1.97-1.87 (m, 5H), 1.59 (m, 4H).55s ¹H-NMR (400 MHz, MeOH-d4): δ ppm 1.74-1.73 (m, 4H), 2.13-2.07 (m,1H), 2.52-2.46 (m, 1H), 3.60-3.55 (m, 1H), 3.70-3.66 (m, 2H), 4.55-4.50(m, 1H), 5.44 (s, 2H), 6.66-6.63 (m, 1H), 7.74-7.69 (m, 2H), 7.88-7.80(m, 4H), 7.96-7.92 (m, 1H) 55t ¹H NMR (400 MHz, MeOH-d4): δ ppm8.03-8.05 (m, 1H), 7.95 (s, 1H), 7.84-7.86 (m, 1H), 7.71-7.73 (m, 2H),7.60-7.62 (m, 2H), 7.43-7.45 (m, 1H), 6.62-6.65 (m, 2H), 5.57 (s, 1H),4.05-4.10 (m, 1H), 3.61-3.70 (m, 3H), 3.42-3.52 (m, 3H), 3.09-3.12 (m,1H), 2.29-2.36 (m, 1H), 2.02-2.07 (m, 1H), 1.60 (m, 4H) 55u ¹H NMR (400MHz, DMSO-d6): δ ppm 8.02 (s, 1H), 7.93-7.98 (m, 2H), 7.76-7.78 (m, 2H),7.59-7.63 (m, 3H), 6.63-6.73 (m, 2H), 5.55 (s, 1H), 3.74-3.79 (m, 1H),3.61 (s, 3H), 3.32-3.47 (m, 5H), 2.89-3.07 (m, 2H), 2.08-2.14 (m, 1H),1.73-1.80 (m, 1H), 1.41 (m, 4H). 55v ¹H NMR (400 MHz, MeOH-d4): δ ppm7.62 (d, 2H, J = 8.0), 7.56 (d, 2H, J = 8.0), 7.45 (m, 2H), 6.93 (d, 1H,J = 8.0), 6.62 (q, 1H, J = 8.0), 5.56 (s, 1H), 4.07 (t, 1H, J = 8.0),3.64δ3.58 (m, 2H), 3.52-3.45 (m, 2H), 3.24 (d, 1H, J = 12.0), 3.11 (d,1H, J = 8.0 Hz), 3.01 (t, 2H, J = 8.0), 2.59-2.57 (m, 2H), 2.32 (dd, 1H,J = 12.0, 8.0), 2.05 (dd, 1H, J = 12.0, 8.0), 1.58 (s, 4H), 1.28 (s, 1H)55w ¹H NMR (400 MHz, DMSO-d6): δ 1.59 (m, 4 H), 2.05-2.01 (m, 1 H, J =11.6 Hz), 2.32-2.28 (m, 1 H, J = 11.6 Hz), 3.11-3.08 (d, 1 H), 3.25-3.22(d, 1 H), 3.50-3.47 (m, 2 H), 3.68-3.65 (m, 2 H), 4.08-4.04 (q, 1 H),5.57 (s, 1 H), 6.66-6.65 (q, 1 H), 8.10 (s, 1 H), 7.61-7.60 (m, 3 H, J =8.6 Hz), 7.71-7.69 (m, 3 H, J = 8.6 Hz), 8.01 (s, 1 H) 55x ¹H NMR (400MHz, MeOH-d4): δ ppm 1.61 (d, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.5, 7.3Hz, 1H), 2.35 (dd, J = 13.5, 9.2 Hz, 1H), 2.56 (s, 3H), 3.15 (d, J =11.8 Hz, 1H), 3.25 (d, J = 11.7 Hz, 1H), 3.54 (m, 5H), 3.99 (s, 3H),4.17 (t, J = 8.3 Hz, 1H), 5.00 (s, 1H), 6.66 (q, J = 7.1 Hz, 1H), 7.53(d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.70 (m, 3H), 7.91 (s,1H) 55y ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54 (m, 4 H), 2.10 (m, 1 H),2.26 (m, 4 H), 3.04 (m, 1 H), 3.17 (m, 1 H), 3.40 (m, 2 H), 3.56 (m, 2H), 3.69 (s, 3 H), 4.07-4.03 (m, 1 H), 6.65-6.59 (m, 1 H), 6.93 (s, 1H), 7.37-7.34 (m, 1 H), 7.45-7.42 (m, 1 H), 7.57-7.55 (m, 2 H),7.72-7.68 (m, 3 H) 55z ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.72-7.63 (m,4H), 7.45 (s, 1H), 7.40 (s, 1H), 7.18 (s, 1H), 6.66 (q, 1H, J = 8.0),4.30 (d, 1H, J = 8.0), 3.91 (s, 3H), 3.66 (s, 2H), 3.55 (s, 2H), 3.26(s, 1H), 3.19 (d, 1H, J = 12.0 Hz), 2.43-2.37 (m, 1H), 2.10-2.05 (m,1H), 1.65 (s, 5H), 1.28 (s, 1H) 55aa ¹H NMR (400 MHz, MeOH-d4): δ ppm7.94 (d, 1H, J = 4.0), 7.71 (d, 1H, J = 4.0), 7.53-7.50 (m, 2H), 6.82(q, 1H, J = 8.0), 6.41 (d, 1H, J = 4.0), 5.68 (d, 1H, J = 4.0), 4.41 (s,1H), 3.09 (s, 1H), 2.75 (t, 2H, J = 8.0), 2.46 (d, 1H, J = 16.0), 2.38(s, 3H), 2.22 (dd, 1H, J = 16.0, 8.0), 1.23-1.19 (m, 3H) 55ab ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.60 (m, 4 H), 2.03-2.05 (m, 1 H), 2.33-2.32(m, 1 H), 3.14-3.11 (d, 1 H, J = 11.9 Hz), 3.26-3.23 (d, 1 H, J = 11.9Hz), 3.52-3.47 (m, 2 H), 3.65-3.54 (m, 2 H), 4.10-4.06 (m, 1H), 5.57 (s,1 H), 6.65-6.64 (q, 1 H), 7.16-7.14 (d, 2 H, J = 8.2 Hz), 7.51-7.44 (dd,2 H, J = 8.2 Hz), 7.51 (s, 1 H), 7.60-7.57 (d, 2 H, J = 8.3 Hz),7.65-7.63 (d, 2 H, J = 8.3 Hz) 55ac ¹H NMR (400 MHz, MeOH-d4): δ ppm7.72-7.69 (m, 3 H), 7.58-7.56 (m, 2 H), 7.38 (s, 2 H), 7.02 (m, 1 H),6.61 (m, 1 H), 4.23 (m, 1 H), 3.65 (m, 2 H), 3.48 (m, 2 H), 3.30 (m, 1H), 3.14 (m, 1 H), 2.31 (m, 4H), 2.06 (m, 1 H), 1.62 (s, 4 H). 55ad ¹HNMR (400 MHz, MeOH-d4): δ ppm 8.08 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2Hz, 2H), 7.67-7.65 (m, 3H), 7.46 (m, 1H), 6.67-6.61 (m, 1H), 4.47 (m,1H), 3.87 (s, 3H), 3.73-3.52 (m, 4H), 3.27-3.22 (m, 2H), 2.50-2.44 (m,1H), 2.33 (s, 3H), 2.12-2.06 (m, 1H), 1.68 (m, 4H). 55ae ¹H NMR (400MHz, DMSO-d6): δ ppm 1.22 (d, J = 5.3 Hz, 2H), 1.42 (m, 4H), 1.82 (d, J= 13.2 Hz, 1H), 1.98 (dd, J = 17.4, 8.5 Hz, 1H), 2.91 (m, 1H), 3.03 (d,J = 11.0 Hz, 1H), 3.55 (s, 1H), 3.68 (s, 1H), 3.80 (s, 1H), 5.62 (s,1H), 6.13 (s, 2H), 6.49 (d, J = 9.6 Hz, 1H), 6.75 (q, J = 7.3 Hz, 1H),7.67 (m, 4H), 7.83 (dd, J = 22.1, 8.1 Hz, 3H), 8.09 (d, J = 9.5 Hz, 1H)55af ¹H NMR (400 MHz, MeOH-d4): δ ppm 8.01 (d, J = 2.6 Hz, 1H), 7.89(dd, J = 2.72, 6.8 Hz, 1H), 7.58 (m, 4H), 6.64 (m, 2H), 5.56 (s, 1H),4.08 (m, 1H), 3.64 (s, 3H), 3.53 (m, 4H), 3.12 (m, 2H), 2.33 (m, 1H),2.06 (m, 1H), 1.60 (m, 4H). 55ag ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.92(d, J = 8.8 Hz, 1H), 7.65 (dd, J1 = 8.4 Hz, J2 = 31.9 Hz, 4H), 7.17-7.14(m, 2H), 6.66-6.63 (m, 1H), 4.14-4.10 (m, 1H), 3.66-3.59 (m, 2H),3.54-3.43 (m, 2H), 3.26-3.24 (m, 1H), 3.15-3.12 (m, 1H), 2.37-2.32 (m,1H), 2.08-2.03 (m, 1H), 1.61 (m, 4H) 55ah ¹H NMR (400 MHz, MeOH-d4): δppm 8.16 (d, J = 8.92 Hz, 1H), 8.02 (d, J = 1.56 Hz, 1H), 7.93-7.86 (m,2H), 7.76 (d, J = 8.16 Hz, 2H), 7.64 (d, J = 8.08 Hz, 2H), 6.96 (d, J =8.88 Hz, 1H), 6.66 (q, J = 7.12 Hz, 1H), 5.57 (s, 1H), 4.06 (s, 3H),3.97 (m, 1H), 3.64 (m, 2H), 3.47 (m, 2H), 3.17 (d, J = 10.92 Hz, 1H),3.00 (d, J = 12.04 Hz, 1H), 2.26 (m, 1H), 2.01 (m, 1H), 1.58 (s, 4H)55ai ¹H NMR (400 MHz, MeOH-d4): δ ppm 8.06 (d, J = 8.76 Hz, 1H), 8.01(s, 1H), 7.93 (s, 2H), 7.76 (d, J = 8.04 Hz, 2H), 7.64 (d, J = 8.16 Hz,2H), 7.31 (d, J = 8.76 Hz, 1H), 6.68 (q, J = 8.48 Hz, 1H), 5.58 (s, 1H),4.08 (m, 1H), 3.63-3.50 (m, 4H), 3.24 (d, J = 11.64 Hz, 1H), 3.12 (d, J= 11.64 Hz, 1H), 2.68 (s, 3H), 2.31 (m, 1H), 2.05 (m, 1H), 1.59 (m, 4H).55aj ¹H NMR (400 MHz, MeOH-d4): δ ppm 67.67 (d, 2H, J = 8.0), 7.61-7.57(m, 4H), 7.51 (s, 1H), 7.20 (d, 1H, J = 8.0), 6.63 (q, 1H, J = 8.0),4.29 (t, 1H, J = 12.0), 3.67δ3.58 (m, 2H), 3.53-3.48 (m, 2H), 3.38 (s,3H), 3.27 (d, 1H, J = 12.0), 3.19 (d, 1H, J = 8.0 Hz), 2.99-2.95 (m,2H), 2.65-2.63 (m, 2H), 2.40 (dd, 1H, J = 12.0, 8.0), 2.09 (dd, 1H, J =12.0, 8.0), 1.66 (s, 5H), 1.31 (s, 2H) 55ak ¹H NMR (400 MHz, MeOH-d4): δppm 1.52-1.67 (m, 4 H) 2.05 (dd, J = 13.42, 7.13 Hz, 1 H) 2.32 (dd, J =13.54, 9.30 Hz, 1 H) 3.07-3.16 (m, 1 H) 3.24 (d, J = 11.76 Hz, 1 H)3.38-3.55 (m, 2 H) 3.56-3.76 (m, 2 H) 4.10 (t, J = 8.18 Hz, 1 H) 5.56(s, 1 H) 6.63 (q, J = 6.96 Hz, 1 H) 7.06 (qd, J = 5.74, 3.29 Hz, 1 H)7.35 (dd, J = 9.30, 1.44 Hz, 1 H) 7.38-7.48 (m, 2 H) 7.55-7.69 (m, 4 H)55al ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J = 4.59 Hz, 4 H) 2.04(dd, J = 13.50, 7.30 Hz, 1 H) 2.31 (dd, J = 13.30, 9.01 Hz, 1 H)3.05-3.25 (m, 2 H) 3.37-3.53 (m, 2 H) 3.54-3.69 (m, 2 H) 3.81 (s, 3 H)4.05 (dd, J = 9.18, 7.32 Hz, 1 H) 5.54 (s, 1 H) 6.61 (q, J = 7.29 Hz, 1H) 6.89 (dd, J = 7.83, 2.12 Hz, 1 H) 7.05-7.21 (m, 2 H) 7.26-7.38 (m, 1H) 7.46-7.68 (m, 4 H) 55am ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.63 (d, J =5.08 Hz, 4 H) 2.08 (dd, J = 13.32, 7.18 Hz, 1 H) 2.35 (dd, J = 13.32,9.22 Hz, 1 H) 3.07-3.20 (m, 1 H) 3.27 (d, J = 11.71 Hz, 1 H) 3.40-3.58(m, 2 H) 3.59-3.80 (m, 2 H) 4.11 (t, J = 7.96 Hz, 1 H) 5.58 (s, 1 H)6.68 (d, J = 7.13 Hz, 1 H) 7.10 (dt, J = 6.00, 2.95 Hz, 1 H) 7.38 (d, J= 10.35 Hz, 1 H) 7.42-7.52 (m, 2 H) 7.56-7.79 (m, 4 H) 55an ¹H NMR (400MHz, MeOH-d4): δ ppm 1.48-1.66 (m, 4 H) 2.01 (dd, J = 13.37, 7.17 Hz, 1H) 2.28 (dd, J = 13.35, 9.20 Hz, 1 H) 3.06 (d, J = 11.71 Hz, 1 H) 3.20(d, J = 11.67 Hz, 1 H) 3.35-3.52 (m, 2 H) 3.53-3.69 (m, 2 H) 3.81 (s, 3H) 4.02 (dd, J = 9.15, 7.20 Hz, 1 H) 5.53 (s, 1 H) 6.61 (q, J = 7.21 Hz,1 H) 6.89 (dd, J = 8.20, 2.49 Hz, 1 H) 7.06-7.21 (m, 2 H) 7.26-7.38 (m,1 H) 7.47-7.68 (m, 4 H) 55ao ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.63-1.87(m, 4 H) 2.10 (dd, J = 13.72, 8.69 Hz, 1 H) 2.48-2.62 (m, 1 H) 3.33 (s,0 H) 3.52-3.81 (m, 4 H) 3.84 (s, 3 H) 4.55 (t, J = 8.81 Hz, 1 H) 5.93(s, 0 H) 6.59 (d, J = 6.25 Hz, 1 H) .71 (dt, J = 10.75, 2.26 Hz, 1 H)6.90-7.02 (m, 2 H) 7.51-7.80 (m, 4 H). 55ap ¹H NMR (400 MHz, MeOH-d4): δppm 1.63-1.85 (m, 4 H) 2.10 (dd, J = 13.64, 8.66 Hz, 1 H) 2.50 (dd, J =13.64, 8.81 Hz, 1 H) 3.51-3.88 (m, 5 H) 4.55 (t, J = 8.71 Hz, 1 H) 5.93(s, 1 H) 6.63 (q, J = 6.61 Hz, 1 H) 6.96 (tt, J = 9.06, 2.31 Hz, 1 H)7.20-7.33 (m, 2 H) 7.62-7.80 (m, 4 H). 55aq ¹H NMR (400 MHz, MeOH-d4): δppm 1.60-1.87 (m, 4 H) 2.09 (dd, J = 13.64, 8.76 Hz, 1 H) 2.50 (dd, J =13.59, 8.86 Hz, 1 H) 3.51-3.79 (m, 4 H) 3.81 (s, 3 H) 4.56 (t, J = 8.74Hz, 1 H) 5.88-5.99 (m, 1 H) 5.93 (s, 1 H) 6.57 (d, J = 6.39 Hz, 1 H)6.94-7.04 (m, 2 H) 7.50-7.70 (m, 6 H) 55ar ¹H NMR (400 MHz, MeOH-d4): δppm 1.67-1.87 (m, 4 H) 2.10 (dd, J = 13.64, 8.71 Hz, 1 H) 2.51 (dd, J =13.59, 8.86 Hz, 1 H) 3.54-3.77 (m, 4 H) 3.78 (s, 4 H) 4.57 (t, J = 8.76Hz, 1 H) 5.95 (s, 1 H) 6.59 (q, J = 6.22 Hz, 1 H) 7.00 (td, J = 7.46,0.95 Hz, 1 H) 7.06 (d, J = 8.10 Hz, 1 H) 7.19-7.38 (m, 2 H) 7.48-7.66(m, 4 H) 55as ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60-1.86 (m, 4 H) 2.10(dd, J = 13.64, 8.66 Hz, 1 H) 2.50 (dd, J = 13.62, 8.83 Hz, 1 H)3.53-3.87 (m, 4 H) 4.54 (t, J = 8.71 Hz, 1 H) 5.93 (s, 0 H) 6.64 (q, J =6.65 Hz, 1 H) 7.61-7.72 (m, 4 H) 7.73-7.80 (m, 2 H) 7.84-7.94 (m, 2 H)55at ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.67-1.84 (m, 4 H) 2.10 (dd, J =13.67, 8.69 Hz, 1 H) 2.51 (dd, J = 13.69, 8.81 Hz, 1 H) 3.55-3.82 (m, 4H) 4.56 (t, J = 8.76 Hz, 1 H) 5.95 (s, 1 H) 6.63 (q, J = 6.56 Hz, 1 H)7.29 (dt, J = 8.19, 1.15 Hz, 1 H) 7.48-7.58 (m, 2 H) 7.61-7.76 (m, 5 H)55au ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.39 (t, J = 7.00 Hz, 3 H)1.65-1.86 (m, 4 H) 2.09 (dd, J = 13.64, 8.76 Hz, 1 H) 2.50 (dd, J =13.62, 8.79 Hz, 1 H) 3.51-3.84 (m, 4 H) 4.07 (q, J = 6.98 Hz, 2 H) 4.57(t, J = 8.74 Hz, 1 H) 5.94 (s, 1 H) 6.61 (q, J = 6.57 Hz, 1 H) 6.82-6.95(m, 1 H) 7.06-7.20 (m, 2 H) 7.28-7.43 (m, 1 H) 7.55-7.73 (m, 4 H) 55av¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (d, J = 6.05 Hz, 6 H) 1.65-1.86(m, 4 H) 2.09 (dd, J = 13.67, 8.69 Hz, 1 H) 2.50 (dd, J = 13.64, 8.86Hz, 1 H) 3.48-3.85 (m, 4 H) 4.55 (t, J = 8.71 Hz, 1 H) 4.65 (dt, J =12.08, 6.06 Hz, 1 H) 5.92 (s, 1 H) 6.59 (q, J = 6.43 Hz, 1 H) 6.91 (dd,J = 8.22, 1.93 Hz, 1 H) 7.11 (t, J = 2.03 Hz, 1 H) 7.15 (d, J = 7.71 Hz,1 H) 7.29-7.39 (m, 1 H) 7.56-7.73 (m, 4 H) 55aw ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.62-1.93 (m, 4 H) 2.11 (dd, J = 13.69, 8.76 Hz, 1 H)2.54 (dd, J = 13.69, 8.86 Hz, 1 H) 3.46-4.00 (m, 4 H) 4.59 (t, J = 8.74Hz, 1 H) 6.01 (s, 1 H) 6.74 (q, J = 6.65 Hz, 1 H) 7.75-8.02 (m, 4 H)8.20 (dd, J = 8.22, 5.78 Hz, 1 H) 8.87 (d, J = 5.71 Hz, 1 H)8.97 (dt, J= 8.27, 1.72 Hz, 1 H) 9.24 (d, J = 2.00 Hz, 1 H) 55ax ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.64-1.90 (m, 4 H) 2.11 (dd, J = 13.67, 8.79 Hz, 1 H)2.52 (dd, J = 13.64, 8.86 Hz, 1 H) 3.49-4.02 (m, 4 H) 4.57 (t, J = 8.71Hz, 1 H) 6.01 (s, 1 H) 6.76 (d, J = 6.54 Hz, 1 H) 7.85 (d, J = 8.35 Hz,2 H) 8.09 (d, J = 8.49 Hz, 2 H) 8.33-8.54 (m, 2 H) 8.80-8.99 (m, 2 H)55ay ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.56-1.91 (m, 4 H) 2.10 (dd, J =13.69, 8.66 Hz, 1 H) 2.51 (dd, J = 13.81, 8.83 Hz, 1 H) 3.53-3.94 (m, 5H) 4.56 (dt, J = 8.48, 4.37 Hz, 1 H) 5.89-6.14 (m, 1 H) 6.51-6.82 (m, 1H) 7.48-8.01 (m, 4 H) 9.19 (s, 1 H) 9.24 (s, 1 H) 55az ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.60 (t, J = 5.08 Hz, 4 H) 2.00 (s, 2 H) 2.03-2.13 (m, 1H) 2.26-2.39 (m, 1 H) 2.52-2.64 (m, 4 H) 3.07-3.18 (m, 1 H) 3.26 (d, J =11.71 Hz, 1 H) 3.39-3.57 (m, 2 H) 3.57-3.77 (m, 2 H) 4.01-4.20 (m, 1 H)5.58 (s, 1 H) 6.67 (s, 1 H) 7.40 (dd, J = 8.49, 1.07 Hz, 1 H) 7.59-7.68(m, 3 H) 7.69-7.79 (m, 3 H) 55ba ¹H NMR (400 MHz, MeOH-d4): δ ppm1.47-1.74 (m, 4 H) 1.99-2.13 (m, 1 H) 2.26-2.40 (m, 1 H) 2.55 (s, 3 H)3.07-3.19 (m, 1 H) 3.21 3.29 (m, 1H) 3.48 (d, J = 4.88 Hz, 2 H) 3.65 (d,J = 3.32 Hz, 2 H) 4.01 (s, 3 H) 4.10 (dd, J = 8.98, 7.22 Hz, 1 H) 5.59(s, 1 H) 6.69 (d, J = 7.03 Hz, 1 H) 7.41 (dd, J = 8.49, 1.07 Hz, 1 H)7.58-7.70 (m, 3 H) 7.70-7.84 (m, 3 H) 55bb ¹H NMR (400 MHz, MeOH-d4): δppm 1.58 (br. s., 4 H) 1.95-2.09 (m, 1 H) 2.24-2.38 (m, 1 H) 2.63 (s, 3H) 3.01-3.14 (m, 1 H) 3.17 3.25 (m, 1 H) 3.38-3.54 (m, 2 H) 3.55-3.74(m, 2H) 55bc ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (br. s., 4 H)1.97-2.09 (m, 1 H) 2.24-2.36 (m, 1 H) 3.07 (s, 3 H) 3.18-3.27 (m, 1 H)3.55 (s, 4 H) 3.60-3.75 (m, 2 H) 3.96-4.07 (m, 1 H) 5.59 (s, 1 H),6.61-6.75 (m, 1 H) 7.54-7.61 (m, 1 H) 7.66 (s, 3 H) 7.72 (s, 2 H)7.95-8.08 (m, 1 H) 55bd ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.50-1.68 (m, 4H) 1.86-2.01 (m, 1 H) 2.11-2.28 (m, 1 H) 2.77-2.91 (m, 1 H) 3.04-3.13(m, 1 H) 3.40-3.57 (m, 2 H) 3.59-3.74 (m, 2 H) 3.76-3.88 (m, 1 H)5.54-5.66 (m, 1 H) 6.61-6.79 (m, 1 H) 7.67-7.77 (m, 2 H) 7.81-7.97 (m, 3H) 7.99-8.09 (m, 1 H) 8.16-8.27 (m, 2 H) 8.41-8.53 (m, 1 H) 9.21-9.33(m, 1 H) 55be ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.50-1.65 (m, 4 H)1.92-2.00 (m, 1 H) 2.14-2.28 (m, 1 H) 2.84-2.94 (m, 1 H) 3.04-3.16 (m, 1H) 3.40-3.57 (m, 2 H) 3.58-3.73 (m, 2 H) 3.79-3.91 (m, 1 H) 5.59 (s, 1H) 6.62-6.78 (m, 1 H) 7.64-7.75 (m, 2 H) 7.86 (d, J = 8.59 Hz, 3 H)8.01-8.09 (m, 1 H) 8.10-8.20 (m, 1 H) 8.35-8.42 (m, 1 H) 8.43-8.48 (m, 1H) 9.25-9.37 (m, 1 H) 55bf ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (br.s., 4 H) 1.94-2.04 (m, 1 H) 2.28 (s, 7 H) 2.92-3.06 (m, 1 H) 3.11-3.23(m, 1 H) 3.53 (s, 4 H) 3.59-3.75 (m, 2 H) 3.89-4.02 (m, 1 H) 5.58 (s, 1H) 6.60-6.70 (m, 1 H) 7.43 (s, 2 H) 7.57-7.74 (m, 6 H) 55bg ¹H NMR (400MHz, MeOH-d4): δ ppm 1.56 (d, J = 4.69 Hz, 4 H) 1.78-1.95 (m, 1 H)2.07-2.22 (m, 1 H) 2.69-2.83 (m, 1 H) 2.96-3.09 (m, 1 H) 3.38-3.54 (m, 2H) 3.56-3.69 (m, 2 H) 3.70-3.79 (m, 1 H) 5.57 (s, 1 H) 6.59-6.77 (m, 1H) 7.51-7.61 (m, 1 H) 7.68 (d, J = 8.00 Hz, 2 H) 7.83 (d, J = 8.20 Hz, 2H) 8.11 (s, 2 H) 8.20 (s, 1 H) 8.38-8.50 (m, 1 H) 8.77-8.92 (m, 1 H)55bh ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4 H) 1.84-2.03 (m, 1H) 2.12-2.29 (m, 1 H) 2.91 (s, 1 H) 3.04-3.16 (m, 1 H) 3.38-3.55 (m, 2H) 3.56-3.73 (m, 2 H) 3.78-3.96 (m, 1 H) 5.58 (s, 1 H) 6.60-6.80 (m, 1H) 7.47-7.58 (m, 1 H) 7.69 (d, J = 8.20 Hz, 2 H) 7.83 (d, J = 8.20 Hz, 2H) 7.93 (d, J = 1.17 Hz, 1 H) 8.02 (d, J = 8.59 Hz, 1 H) 8.25 (s, 1 H)8.37 (s, 1 H) 8.87 (d, J = 2.93 Hz, 1 H) 55bi ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.56 (d, J = 5.08 Hz, 4 H) 1.76-1.88 (m, 1 H) 2.05-2.20 (m, 1H) 2.63-2.81 (m, 1 H) 2.94-3.07 (m, 1 H) 3.37-3.54 (m, 2 H) 3.55-3.79(m, 3 H) 5.58 (s, 1H) 6.61-6.78 (m, 1 H) 7.71 (d, J = 8.20 Hz, 2 H) 7.86(d, J = 8.40 Hz, 2 H) 8.17 (s, 2 H) 8.32 (s, 1 H) 8.89 (dd, J = 12.98,1.66 Hz, 2 H) 55bj ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54-1.72 (m, 4 H)2.01-2.13 (m, 1 H) 2.27-2.41 (m, 1 H) 3.06-3.16 (m, 3 H) 3.18 (s, 3 H)3.22-3.30 (m, 1 H) 3.41-3.59 (m, 2 H) 3.67 (s, 4 H) 4.02-4.16 (m, 1 H)5.53-5.66 (m, 1 H) 6.61-6.74 (m, 1 H) 7.54-7.57 (m, 1 H) 7.61-7.67 (m, 3H) 7.70-7.80 (m, 2 H) 7.96-8.06 (m, 1 H) 55bk ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.54-1.72 (m, 4 H) 2.05-2.18 (m, 1 H) 2.29-2.43 (m, 1 H) 3.08-3.20(m, 1 H) 3.24-3.29 (m, 1 H) 3.43-3.76 (m, 4 H) 4.05-4.17 (m, 1 H)5.57-5.67 (m, 1 H) 6.64-6.79 (m, 1 H) 7.65-7.76 (m, 2 H) 7.83-7.94 (m, 2H) 8.08-8.19 (m, 1 H) 8.32-8.48 (m, 2 H) 9.21-9.33 (m, 1 H) 9.56-9.67(m, 1 H) 55bp ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (q, J = 5.9, 5.2 Hz,4H), 1.98 (m, 5H), 2.32 (dd, J = 13.4, 9.3 Hz, 1H), 3.12 (d, J = 11.8Hz, 1H), 3.25 (d, J = 11.7 Hz, 1H), 3.50 (m, 4H), 3.61 (m, 4H), 4.08(dd, J = 9.2, 7.2 Hz, 1H), 5.57 (s, 1H), 6.67 (q, J = 7.1 Hz, 1H), 7.61(ddd, J = 356.8, 7.9, 5.7 Hz, 4H), 7.71 (m, 4H) 55cc ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.09 (d, J = 1.2 Hz, 0H), 1.28 (s, 0H), 1.61 (q, J = 5.3Hz, 0H), 1.92 (m, 0H), 2.05 (dd, J = 13.3, 7.3 Hz, 0H), 2.32 (m, 0H),3.10 (s, 0H), 3.29 (s, 2H), 3.53 (s, 0H), 3.65 (s, 1H), 3.80 (dd, J =16.8, 1.2 Hz, 0H), 4.07 (t, J = 8.2 Hz, 0H), 4.89 (d, J = 3.8 Hz, 0H),5.56 (d, J = 1.2 Hz, 0H), 5.99 (m, 0H), 6.60 (m, 0H), 7.21 (dd, J = 8.4,1.2 Hz, 0H), 7.48 (d, J = 1.2 Hz, 1H) 55ce ¹H NMR (400 MHz, DMSO-d6): δppm 1.58 (q, J = 6.7, 6.1 Hz, 4H), 1.94 (dd, J = 13.2, 9.1 Hz, 1H), 2.39(dd, J = 13.3, 8.6 Hz, 1H), 3.20 (s, 2H), 3.80 (m, 3H), 4.54 (t, J = 8.4Hz, 1H), 5.74 (s, 1H), 6.31 (s, 2H), 6.90 (q, J = 7.2 Hz, 1H), 7.49 (t,J = 6.5 Hz, 3H), 7.76 (m, 6H), 9.01 (dt, J = 21.8, 11.9 Hz, 1H), 9.74(d, J = 11.9 Hz, 1H) 55cg ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.59 (m, 4H),2.00 (s, 7H), 2.41 (m, 1H), 3.20 (s, 2H), 3.60 (m, 4H), 3.83 (m, 1H),4.53 (d, J = 8.7 Hz, 1H), 5.74 (s, 1H), 6.34 (dd, J = 28.1, 14.7 Hz,2H), 6.91 (q, J = 7.4 Hz, 1H), 7.24 (m, 5H), 7.67 (d, J = 7.8 Hz, 2H),8.99 (s, 1H), 9.77 (d, J = 8.4 Hz, 1H) 55cj ¹H NMR (400 MHz, DMSO-d6): δppm 1.29 (d, J = 6.8 Hz, 6H), 1.58 (m, 4H), 1.94 (dd, J = 13.2, 9.2 Hz,1H), 2.39 (dd, J = 13.4, 8.6 Hz, 1H), 2.99 (hept, J = 7.1 Hz, 1H), 3.19(s, 2H), 3.59 (m, 4H), 4.55 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 6.28 (m,2H), 6.81 (q, J = 7.4 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.65 (m, 4H),7.78 (d, J = 8.0 Hz, 2H), 8.97 (d, J = 13.6 Hz, 1H), 9.76 (s, 1H) 55ck¹H NMR (400 MHz, DMSO-d6): δ ppm 0.99 (s, 1H), 1.31 (d, J = 6.9 Hz, 7H),1.58 (m, 4H), 1.94 (dd, J = 13.2, 9.2 Hz, 1H), 2.39 (dd, J = 13.4, 8.6Hz, 1H), 3.02 (hept, J = 7.2 Hz, 1H), 3.19 (s, 2H), 3.55 (ddd, J = 19.7,12.2, 5.9 Hz, 2H), 3.86 (s, 2H), 4.05 (s, 1H), 4.54 (q, J = 8.9, 6.7 Hz,1H), 5.73 (s, 1H), 6.31 (m, 2H), 6.81 (q, J = 7.3 Hz, 1H), 7.46 (m, 5H),7.65 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 8.96 (dt, J = 20.8,8.6 Hz, 1H), 9.77 (d, J = 8.5 Hz, 1H) 55cp ¹H NMR (400 MHz, DMSO-d6): δppm 1.29 (s, 1H), 1.57 (dd, J = 9.4, 5.0 Hz, 12H), 1.94 (dd, J = 13.3,9.1 Hz, 3H), 2.28 (s, 9H), 2.41 (m, 4H), 2.61 (d, J = 7.4 Hz, 1H), 3.19(s, 7H), 3.59 (m, 13H), 4.15 (s, 1H), 4.55 (d, J = 8.4 Hz, 4H), 5.75 (s,3H), 6.38 (m, 5H), 6.87 (q, J = 7.4 Hz, 3H), 7.46 (m, 22H), 8.98 (m,3H), 9.76 (m, 3H) 55cq ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (m, 4H),2.05 (m, 1H), 2.34 (s, 7H), 3.12 (d, J = 11.5 Hz, 1H), 3.24 (d, J = 11.5Hz, 1H), 3.49 (m, 2H), 3.64 (dq, J = 12.6, 6.5, 4.7 Hz, 2H), 4.08 (t, J= 8.2 Hz, 1H), 5.56 (s, 1H), 6.64 (q, J = 7.1 Hz, 1H), 6.99 (s, 1H),7.21 (s, 2H), 7.59 (m, 5H) 55cr ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.29(s, 1H), 1.58 (dq, J = 11.6, 7.5, 7.1 Hz, 11H), 1.94 (dd, J = 13.3, 9.1Hz, 3H), 2.15 (s, 0H), 2.39 (dd, J = 13.3, 8.6 Hz, 3H), 2.61 (d, J = 8.8Hz, 3H), 3.05 (s, 0H), 3.19 (s, 6H), 3.40 (s, 1H), 3.54 (h, J = 6.4 Hz,3H), 3.81 (m, 4H), 4.01 (dd, J = 19.9, 11.7 Hz, 1H), 4.16 (s, 1H), 4.54(t, J = 8.6 Hz, 3H), 5.73 (s, 3H), 6.28 (d, J = 15.5 Hz, 5H), 6.81 (q, J= 7.3 Hz, 3H), 7.63 (m, 11H), 7.86 (dd, J = 17.4, 7.8 Hz, 8H), 8.99 (dq,J = 23.7, 15.7, 12.4 Hz, 2H), 9.72 (s, 3H) 55cs ¹H NMR (400 MHz,DMSO-d6): δ ppm 1.57 (m, J = 8.0, 6.2 Hz, 8H), 1.94 (dd, J = 13.2, 9.2Hz, 2H), 2.23 (s, 6H), 2.34 (s, 8H), 3.20 (s, 5H), 3.57 (dp, J = 22.0,7.4, 6.0 Hz, 9H), 4.54 (t, J = 8.4 Hz, 3H), 5.76 (s, 2H), 6.34 (d, J =14.9 Hz, 1H), 6.45 (s, 1H), 6.86 (q, J = 7.4 Hz, 2H), 7.18 (m, 6H), 7.56(dd, J = 46.1, 7.8 Hz, 8H), 8.99 (m, 2H), 9.77 (d, J = 15.0 Hz, 2H) 55ct¹H NMR (400 MHz, DMSO-d6): δ ppm 0.97 (t, J = 7.3 Hz, 3H), 1.50 (m, 9H),1.94 (dd, J = 13.3, 9.2 Hz, 1H), 2.39 (dd, J = 13.3, 8.6 Hz, 1H), 2.67(q, J = 6.9, 6.2 Hz, 2H), 3.19 (s, 2H), 3.57 (m, 5H), 3.85 (m, 1H), 4.06(d, J = 16.1 Hz, 1H), 4.54 (m, 1H), 5.74 (s, 1H), 6.31 (s, 2H), 6.81 (q,J = 7.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 7.8 Hz, 4H),7.78 (d, J = 8.0 Hz, 2H), 8.96 (m, 1H), 9.73 (d, J = 8.2 Hz, 1H) 55cv ¹HNMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, 1H), 1.38 (s, 1H), 1.58 (qd, J =12.6, 8.1, 7.6 Hz, 11H), 1.95 (m, 8H), 2.43 (m, 5H), 2.94 (t, J = 10.0Hz, 1H), 3.08 (dd, J = 16.3, 7.0 Hz, 1H), 3.19 (s, 6H), 3.33 (s, 8H),3.52 (m, 4H), 3.82 (m, 5H), 4.11 (m, 4H), 4.53 (dt, J = 12.6, 6.0 Hz,3H), 5.75 (s, 2H), 6.20 (s, 1H), 6.28 (d, J = 9.3 Hz, 2H), 6.48 (s, 3H),6.84 (q, J = 7.3 Hz, 2H), 7.56 (s, 1H), 7.93 (m, 21H), 8.98 (dd, J =13.6, 8.0 Hz, 2H), 9.71 (m, 2H) 55cw ¹H NMR (400 MHz, DMSO-d6): δ ppm1.29 (s, 1H), 1.58 (dd, J = 7.3, 4.2 Hz, 8H), 1.94 (dd, J = 13.2, 9.1Hz, 2H), 2.14 (d, J = 1.4 Hz, 0H), 2.40 (s, 8H), 2.49 (d, J = 9.3 Hz,0H), 3.03 (m, 1H), 3.19 (s, 5H), 3.55 (m, 3H), 3.81 (t, J = 8.1 Hz, 0H),4.00 (m, 8H), 4.24 (m, 0H), 4.35 (m, 1H), 4.54 (m, 2H), 5.74 (s, 2H),6.31 (m, 3H), 6.80 (q, J = 7.3 Hz, 2H), 7.34 (d, J = 7.8 Hz, 4H), 7.64(d, J = 8.1 Hz, 8H), 7.78 (m, 4H), 8.99 (q, J = 8.5, 7.4 Hz, 2H), 9.74(s, 2H) 55cx ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, 1H), 1.59 (m,11H), 1.94 (dd, J = 13.3, 9.1 Hz, 3H), 2.43 (s, 11H), 2.61 (d, J = 9.0Hz, 1H), 3.19 (s, 6H), 3.58 (m, 11H), 4.13 (s, 1H), 4.54 (m, 6H), 5.75(s, 2H), 6.26 (s, 1H), 6.34 (s, 1H), 6.42 (s, 2H), 6.81 (q, J = 7.3 Hz,3H), 7.27 (d, J = 7.5 Hz, 3H), 7.58 (m, 20H), 8.98 (s, 3H), 9.77 (d, J =9.9 Hz, 3H) 55db ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.24 (m, 8H), 1.76(dd, J = 12.6, 6.8 Hz, 9H), 2.01 (s, 3H), 2.12 (m, 4H), 2.51 (dd, J =13.6, 8.8 Hz, 3H), 2.63 (td, J = 7.6, 5.4 Hz, 4H), 2.90 (m, 6H), 3.36(d, J = 12.8 Hz, 7H), 3.63 (dt, J = 11.5, 5.0 Hz, 4H), 3.76 (m, 4H),4.11 (qd, J = 7.1, 3.6 Hz, 4H), 4.56 (t, J = 8.7 Hz, 3H), 4.94 (s, 2H),6.62 (dq, J = 19.2, 6.7 Hz, 3H), 7.02 (dt, J = 6.2, 2.0 Hz, 3H), 7.16(m, 2H), 7.38 (m, 2H), 7.65 (m, 9H), 7.84 (m, 1H) 55dc ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.58 (t, J = 5.4 Hz, 4H), 2.02 (dd, J = 13.4, 7.0 Hz,1H), 2.29 (dd, J = 13.4, 9.1 Hz, 1H), 3.08 (d, J = 11.6 Hz, 1H), 3.21(d, J = 11.5 Hz, 1H), 3.46 (ddt, J = 20.6, 13.2, 5.7 Hz, 2H), 3.61 (d, J= 16.6 Hz, 2H), 4.05 (t, J = 8.1 Hz, 1H), 4.94 (s, 10H), 5.58 (s, 1H),6.69 (q, J = 7.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.9 Hz,2H), 8.00 (dd, J = 8.9, 1.9 Hz, 1H), 8.12 (m, 3H), 8.79 (d, J = 2.7 Hz,1H) 55dd ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.29(d, J = 5.8 Hz, 1H), 1.59 (q, J = 5.8, 5.0 Hz, 4H), 1.80 (h, J = 6.9 Hz,2H), 2.04 (dd, J = 13.5, 7.1 Hz, 1H), 2.32 (dd, J = 13.4, 9.2 Hz, 1H),3.11 (d, J = 11.8 Hz, 1H), 3.23 (d, J = 12.0 Hz, 1H), 3.47 (ddt, J =20.6, 13.1, 6.1 Hz, 2H), 3.64 (m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 4.07(dd, J = 9.1, 7.3 Hz, 1H), 5.55 (s, 1H), 6.62 (q, J = 7.1 Hz, 1H), 6.97(m, 2H), 7.56 (m, 6H) 55de ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.15 (t, J =7.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.61 (q, J = 5.9, 5.1 Hz, 4H),2.05 (dd, J = 13.4, 7.2 Hz, 1H), 2.32 (dd, J = 13.4, 9.2 Hz, 1H), 3.11(d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.6 Hz, 1H), 3.35 (m, 3H), 3.56(dddd, J = 47.5, 27.9, 14.5, 7.8 Hz, 6H), 4.07 (dd, J = 9.2, 7.1 Hz,1H), 4.92 (s, 17H), 5.57 (s, 1H), 6.66 (q, J = 7.1 Hz, 1H), 7.46 (m,2H), 7.62 (d, J = 8.1 Hz, 2H), 7.71 (m, 4H) 55df ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (s, 1H), 1.64 (m, 4H), 2.07 (dd, J = 13.5, 7.6 Hz,1H), 2.39 (dd, J = 13.5, 9.0 Hz, 1H), 3.17 (d, J = 11.7 Hz, 1H), 3.27(d, J = 12.0 Hz, 2H), 3.53 (dt, J = 22.9, 7.5 Hz, 2H), 3.67 (td, J =13.8, 13.2, 6.4 Hz, 2H), 4.26 (t, J = 8.3 Hz, 1H), 4.87 (m, 3H), 6.66(q, J = 7.0 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.74 (m, 4H), 7.96 (m,2H) 55dg ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (dd, J = 17.3, 3.8 Hz,2H), 1.62 (m, 4H), 2.06 (dd, J = 13.5, 7.4 Hz, 1H), 2.36 (dd, J = 13.5,9.1 Hz, 1H), 2.93 (s, 3H), 3.15 (d, J = 11.9 Hz, 1H), 3.26 (d, J = 11.6Hz, 1H), 3.51 (m, 2H), 3.64 (dq, J = 12.1, 6.4, 5.1 Hz, 2H), 4.18 (dd, J= 9.1, 7.5 Hz, 1H), 4.93 (d, J = 1.7 Hz, 19H), 6.66 (q, J = 7.1 Hz, 1H),7.63 (d, J = 8.1 Hz, 2H), 7.72 (dd, J = 8.3, 5.9 Hz, 4H), 7.89 (m, 2H)55dh ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (q, J = 6.0, 5.0 Hz, 4H),2.03 (dd, J = 13.4, 7.2 Hz, 1H), 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 2.59(dt, J = 24.2, 5.7 Hz, 6H), 3.10 (d, J = 11.7 Hz, 1H), 3.23 (d, J = 11.9Hz, 1H), 3.62 (m, 10H), 4.06 (dd, J = 9.2, 7.2 Hz, 1H), 4.87 (s, 1H),5.57 (s, 1H), 6.66 (q, J = 7.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.72(m, 4H), 7.91 (m, 2H) 55di ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (d, J =5.5 Hz, 4H), 2.05 (dd, J = 13.4, 7.1 Hz, 1H), 2.32 (dd, J = 13.4, 9.3Hz, 1H), 3.15 (s, 4H), 3.25 (d, J = 11.6 Hz, 1H), 3.50 (dt, J = 20.2,7.0 Hz, 2H), 3.64 (m, 2H), 4.09 (dd, J = 9.2, 7.1 Hz, 1H), 5.58 (s, 1H),6.68 (q, J = 7.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.4 Hz,2H), 7.88 (d, J = 8.4 Hz, 2H), 8.01 (m, 2H) 55dj ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (s, 1H), 1.60 (q, J = 6.4, 5.0 Hz, 4H), 2.03 (dd, J= 13.4, 7.1 Hz, 1H), 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 3.10 (d, J = 11.7Hz, 1H), 3.23 (d, J = 11.8 Hz, 1H), 3.48 (m, 2H), 3.63 (m, 2H), 4.06(dd, J = 9.2, 7.1 Hz, 1H), 5.57 (s, 1H), 6.67 (q, J = 7.1 Hz, 1H), 7.68(m, 4H), 7.79 (m, 2H), 7.96 (m, 2H) 55dk ¹H NMR (400 MHz, MeOH-d4): δppm 1.29 (d, J = 3.6 Hz, 1H), 1.63 (q, J = 5.8 Hz, 5H), 2.07 (dd, J =13.5, 7.5 Hz, 1H), 2.37 (dd, J = 13.5, 9.0 Hz, 1H), 3.04 (s, 3H), 3.15(d, J = 24.6 Hz, 6H), 3.27 (m, 1H), 3.52 (dt, J = 24.6, 8.3 Hz, 2H),3.65 (m, 2H), 4.23 (t, J = 8.1 Hz, 1H), 6.66 (q, J = 7.0 Hz, 1H), 7.51(d, J = 8.1 Hz, 2H), 7.68 (m, 6H) 55dl ¹H NMR (400 MHz, MeOH-d4): δ ppm1.29 (m, 3H), 1.60 (q, J = 6.1, 4.7 Hz, 4H), 2.05 (dd, J = 13.2, 7.0 Hz,1H), 2.32 (dd, J = 13.5, 9.2 Hz, 1H), 3.13 (d, J = 11.6 Hz, 1H), 3.26(m, 5H), 3.48 (ddd, J = 26.8, 12.6, 5.3 Hz, 2H), 3.64 (td, J = 19.2,16.1, 9.2 Hz, 2H), 3.78 (s, 1H), 3.90 (m, 3H), 4.10 (dd, J = 9.2, 7.1Hz, 1H), 4.95 (s, 13H), 5.56 (s, 1H), 6.67 (q, J = 7.0 Hz, 1H), 7.67 (m,7H) 55dm ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4 Hz, 4H), 1.59(d, J = 6.1 Hz, 5H), 1.82 (dq, J = 14.1, 6.6 Hz, 2H), 2.02 (dd, J =13.4, 7.2 Hz, 1H), 2.30 (dd, J = 13.5, 9.2 Hz, 1H), 3.07 (d, J = 11.6Hz, 1H), 3.21 (m, 2H), 3.48 (dt, J = 20.5, 6.6 Hz, 2H), 3.65 (d, J =15.7 Hz, 2H), 4.03 (td, J = 7.7, 6.5, 5.1 Hz, 3H), 4.91 (m, 1H), 5.55(s, 1H), 6.63 (q, J = 7.2 Hz, 1H), 7.13 (t, J = 8.7 Hz, 1H), 7.38 (m,2H), 7.59 (q, J = 8.4 Hz, 4H) 55dn ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28(d, J = 2.6 Hz, 1H), 1.43 (t, J = 6.9 Hz, 3H), 1.60 (q, J = 5.8 Hz, 4H),2.05 (dd, J = 13.1, 7.0 Hz, 1H), 2.33 (dd, J = 13.4, 9.0 Hz, 1H), 3.12(d, J = 11.4 Hz, 1H), 3.25 (d, J = 11.4 Hz, 1H), 3.48 (m, 2H), 3.65 (q,J = 12.5, 10.8 Hz, 2H), 4.11 (dq, J = 16.7, 8.5, 7.7 Hz, 3H), 5.56 (s,1H), 6.63 (q, J = 7.0 Hz, 1H), 7.13 (t, J = 8.6 Hz, 1H), 7.38 (m, 2H),7.59 (q, J = 8.1 Hz, 4H) 55do ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.40 (t,J = 7.0 Hz, 3H), 1.60 (q, J = 5.9, 5.1 Hz, 4H), 2.05 (dd, J = 13.4, 7.2Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, 1H), 3.12 (d, J = 11.7 Hz, 1H),3.24 (d, J = 11.7 Hz, 1H), 3.47 (ddt, J = 20.2, 12.7, 5.6 Hz, 2H), 3.64(m, 2H), 4.07 (p, J = 7.1 Hz, 3H), 5.56 (s, 1H), 6.62 (q, J = 7.1 Hz,1H), 6.97 (m, 2H), 7.57 (m, 6H) 55dp ¹H NMR (400 MHz, MeOH-d4): δ ppm1.28 (s, 1H), 1.64 (d, J = 6.8 Hz, 5H), 2.07 (dd, J = 13.5, 7.6 Hz, 1H),2.38 (dd, J = 13.5, 9.1 Hz, 1H), 3.17 (d, J = 11.8 Hz, 1H), 3.27 (d, J =11.8 Hz, 1H), 3.52 (m, 1H), 3.66 (m, 1H), 4.24 (t, J = 8.3 Hz, 1H), 6.70(p, J = 7.2 Hz, 1H), 7.72 (d, J = 8.1 Hz, 3H), 7.90 (m, 3H), 8.28 (m,3H), 8.53 (m, 1H), 9.31 (d, J = 5.9 Hz, 1H) 55dq ¹H NMR (400 MHz,MeOH-d4): δ ppm 7.62-7.49 (m, 4H), 7.33-7.24 (m, 2H), 6.76 (d, J = 8.3Hz, 1H), 6.62 (q, J = 7.2 Hz, 1H), 5.53 (s, 1H), 4.19-4.12 (m, 2H), 4.08(dd, J = 9.1, 7.3 Hz, 1H), 3.61 (s, 2H), 3.44 (ddt, J = 20.8, 13.4, 6.0Hz, 2H), 3.22 (d, J = 11.7 Hz, 1H), 3.10 (d, J = 11.7 Hz, 1H), 2.80 (t,J = 6.5 Hz, 2H), 2.30 (dd, J = 13.5, 9.2 Hz, 1H), 2.00 (ddd, J = 17.2,12.5, 6.7 Hz, 3H), 1.57 (q, J = 5.9, 4.6 Hz, 4H), 1.27 (s, 1H)

Example 56:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(1,2,3,4-tetrahydroquinoxalin-6-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(a by-product from the N-CBZ deprotection of Example 55bi) using theLiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54-1.72 (m, 4H) 2.07-2.14 (m, 1H)2.29-2.41 (m, 1H) 3.09-3.18 (m, 1H) 3.22-3.29 (m, 1H) 3.36-3.42 (m, 4H)3.43-3.58 (m, 2H) 3.60-3.80 (m, 2H) 4.03-4.17 (m, 1H) 5.49-5.65 (m, 1H)6.50-6.67 (m, 2H) 6.77-6.92 (m, 2H) 7.43-7.63 (m, 4H). LCMS (MH+): 585.

Example 57:(S)-8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(a by-product from the N-CBZ deprotection of Example 55bk) using theLiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4) δ ppm 1.54-1.66 (m, 4H) 1.98-2.08 (m, 1H)2.23-2.34 (m, 1H) 3.02-3.11 (m, 1H) 3.17-3.25 (m, 1H) 3.37-3.54 (m, 2H)3.55-3.72 (m, 2H) 3.97-4.08 (m, 1H) 4.62-4.70 (m, 2H) 5.50-5.58 (m, 1H)6.56-6.66 (m, 1H) 6.86-6.93 (m, 1H) 7.19-7.24 (m, 1H) 7.25-7.31 (m, 1H)7.38-7.44 (m, 1H) 7.51-7.57 (m, 2H) 7.57-7.64 (m, 2H). LCMS (MH+): 583

Example 58:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(1,2,3,4-tetrahydroquinazolin-6-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid

Hydrolysis of (S)-ethyl8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(a by-product from the N-CBZ deprotection of Example 55bk) using theLiOH general method provided the title compound as an off-white solid.

¹H NMR (400 MHz, MeOH-d4) δ ppm 1.57-1.68 (m, 4H) 1.93-2.03 (m, 1H)2.18-2.30 (m, 1H) 2.90-3.01 (m, 1H) 3.12-3.19 (m, 1H) 3.43-3.75 (m, 4H)3.86-3.95 (m, 1H) 4.00-4.07 (m, 2H) 4.15-4.23 (m, 2H) 5.45-5.64 (m, 1H)6.56-6.67 (m, 2H) 7.17-7.23 (m, 1H) 7.27-7.33 (m, 1H) 7.49-7.55 (m, 2H)7.55-7.62 (m, 2H). LCMS (MH+): 585.

Example 59a:(S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

N-CBZ Deprotection was carried out using Method B with(S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (75 mg, product of Step 3, Example 55an) providing the titlecompound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.50-1.68 (m, 4H) 1.96 (s, 2H) 2.04(dd, J=13.35, 7.20 Hz, 1H) 2.31 (dd, J=13.35, 9.10 Hz, 1H) 3.07-3.26 (m,2H) 3.35-3.55 (m, 2H) 3.55-3.73 (m, 2H), 4.06 (dd, J=9.13, 7.17 Hz, 1H)5.52 (s, 1H) 6.57 (q, J=7.11 Hz, 1H) 7.41 (d, J=8.44 Hz, 2H) 7.51-7.58(m, 2H); LCMS (MH+): 531.

Example 59b:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

The title compound was made as described for Example 10e, starting with(R)-2,2,2-trifluoro-1-(naphthalen-2-yl)ethanol.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.20 (dt, J=12.5, 5.3 Hz, 2H), 1.47 (m,3H), 1.88 (dd, J=12.4, 8.0 Hz, 1H), 2.57 (s, 1H), 2.69 (s, 1H), 2.80 (d,J=12.4 Hz, 1H), 3.36 (m, 3H), 3.97 (dt, J=12.3, 5.2 Hz, 2H), 6.05 (s,1H), 6.37 (m, 3H), 7.53 (m, 2H), 7.77 (dd, J=7.5, 1.5 Hz, 1H), 7.93 (m,4H); LCMS (MH+): 562.

Example 59c:(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a solution of 4-bromo-2-methylbenzoic acid (5.0 g, 23.2 mmol) in DMF(50 mL) was added potassium carbonate (6.4 g, 46.4 mmol) and iodomethane(6.6 g, 46.479 mmol). The mixture was stirred at RT for 12 h thendiluted with water and extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. Purification by normal phase silica gel column provided methyl4-bromo-2-methylbenzoate as a colorless oil.

Step 2:

To a solution of methyl 4-bromo-2-methylbenzoate (2 g, 8.7 mmol) in THF(20 mL) was added LAH (663 mg, 17.5 mmol) at 0° C. The mixture wasstirred at RT for 1 h, then diluted with NaOH (1.0M, 10 mL) andextracted with ethyl acetate. The combined organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. Purification bynormal phase silica gel column provided (4-bromo-2-methylphenyl)methanolas a colorless oil.

Step 3:

To the solution of (4-bromo-2-methylphenyl)methanol (1.8 g, 8.1 mmol) inCH₂Cl₂ (20 mL) was added Dess-Martin Periodinane (5.1 g, 12.1 mmol) at0° C. The mixture was stirred at RT for 1 h, then diluted with water,and the solid was removed by filtration. The filtrate was extracted withCH₂Cl₂. The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. Purification by normal phase silicagel column provided 4-bromo-2-methylbenzaldehyde as a yellow oil.

Step 4:

To a solution of 4-bromo-2-methylbenzaldehyde (1.5 g, 7.5 mmol) in THF(20 mL) was added TMSCF₃ (2.2 g, 15.5 mmol) at 0° C. and then TBAF (1.1mL, 1.0 Min THF). The mixture was stirred at RT for 1 h, then dilutedwith HCl (3.0 M, 10 mL), stirred at RT for 1 h and extracted with ethylacetate. The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. Purification by normal phase silicagel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol asan off-white solid.

Step 5:

To a solution of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol (1.8g, 6.7 mmol) in CH₂Cl₂ (20 mL) was added Dess-Martin Periodinane (3.4 g,8.1 mmol) at 0° C. The mixture was stirred at RT for 2 h, then dilutedwith water (10 mL) and filtered. The filtrate was extracted with CH₂Cl₂.The combined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. Purification by normal phase silica gel columnprovided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanone as a yellowoil.

Step 6:

Chiral reduction of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanoneusing the Iridium complex-catalyzed hydrogenation as described forIntermediate 1,(R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanolprovides (R)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol.

Steps 7:

The title compound was prepared as described for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 55an) Steps 4-5.3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolone wasused as the Suzuki coupling partner (CAS#1251731-31-3).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59 (s, 4H), 2.04 (dd,J=13.5, 7.0 Hz, 1H), 2.31 (dd, J=13.3, 9.3 Hz, 1H), 2.65 (s, 3H), 3.10(d, J=11.7 Hz, 1H), 3.23 (d, J=11.5 Hz, 1H), 3.47 (t, J=14.3 Hz, 2H),3.63 (t, J=13.8 Hz, 2H), 4.07 (t, J=8.1 Hz, 1H), 5.56 (s, 1H), 6.87 (q,J=7.0 Hz, 1H), 7.63 (d, J=4.6 Hz, 3H), 8.01 (d, J=8.9 Hz, 1H), 8.12 (m,3H), 8.80 (m, 1H). LCMS (MH+): 611.

Example 59d:(S)-8-(2-amino-6-((R)-1-(2-ethyl-4-(3-fluoroquinolin-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

To a 0° C. solution of LDA (10.7 mL, 21.39 mmol) in THF (20 mL) wasadded 4-bromo-2-methylbenzoic acid (2 g, 9.3 mmol) in THF (5 mL). Themixture was stirred at 0° C. for 1 h, cooled to −70° C., and then MeI(2.3 mL, 37.20 mmol) was added dropwise. The mixture was allowed to warmup to 0° C., stirred for 3 h, then quenched with H₂O, and the pH wasadjusted to 1-2 with 3 N HCl. The mixture was then diluted with waterand extracted with ethyl acetate. The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. Purification bynormal phase silica gel column provided 4-bromo-2-ethylbenzoic acid as awhite solid.

Step 2:

The title compound was prepared as described above for(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(3-fluoroquinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 59c) starting with 4-bromo-2-ethylbenzoic acid in place of4-bromo-2-methylbenzoic acid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.41 (t, J=7.5 Hz, 3H),1.59 (q, J=6.1, 5.6 Hz, 4H), 2.04 (dd, J=13.5, 7.1 Hz, 1H), 2.32 (dd,J=13.4, 9.1 Hz, 1H), 3.01 (dt, J=12.1, 7.0 Hz, 2H), 3.12 (d, J=11.6 Hz,1H), 3.24 (d, J=11.8 Hz, 1H), 3.48 (dt, J=21.5, 6.9 Hz, 2H), 3.62 (m,2H), 4.08 (dd, J=9.1, 7.0 Hz, 1H), 4.94 (s, 15H), 5.56 (s, 1H), 7.00 (q,J=6.9 Hz, 1H), 7.67 (m, 3H), 8.11 (m, 5H), 8.80 (d, J=2.8 Hz, 1H). LCMS(MH+): 626.

Example 60:9-(2-Amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylicacid

Step 1:

To a solution of methyl 3,9-diazaspiro[5.5]undecane-10-carboxylate (30mg, 0.14 mmol) in dioxane (2 mL)/i-PrOH (2 mL) was added4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amine(92 mg, 0.22 mmol), and the reaction was heated at 100° C. undermicrowave for 3 h. The reaction was cooled to RT, and concentrated invacuo. The residue was purified by reversed phase HPLC (MeOH/H₂O/0.5%TFA) to provide methyl9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylateas an off-white solid.

Step 2:

Hydrolysis of methyl9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylateusing the LiOH general method provides the title compound as anoff-white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.22-1.37 (m, 1H) 1.30-1.30 (m, 1H)1.46-1.68 (m, 4H) 1.68-1.90 (m, 2H) 2.29 (dd, J=12.59, 6.83 Hz, 1H) 2.37(d, J=1.90 Hz, 3H) 3.07-3.24 (m, 2H) 3.59-3.90 (m, 4H) 4.03-4.19 (m, 1H)6.29-6.38 (m, 1H) 6.40 (d, J=2.29 Hz, 1H), 6.88-7.02 (m, 1H) 7.52-7.61(m, 2H) 7.65-7.74 (m, 1H) 7.89 (d, J=2.34 Hz, 1H). LCMS (MH+): 581.

Example 61:(S)-8-(2-Amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

A mixture of 4-bromophenol (173 mg, 1.00 mmol),4-chloro-6-(chloromethyl)pyrimidin-2-amine (CAS#: 92311-35-8) (178 mg,1.16 mmol) and K₂CO₃ (175 mg, 1.00 mmol) in DMF (5 mL) was heated to100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo,and the residue taken up in and EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. Purification onnormal phase silica gel (EtOAc/petroleum ether) provided4-((4-bromophenoxy)methyl)-6-chloropyrimidin-2-amine as a white solid.

Step 2:

A mixture of 4-((4-Bromophenoxy)methyl)-6-chloropyrimidin-2-amine (454mg, 1.4 mmol), (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 1.44 mmol) andNaHCO₃ (605 mg, 7 mmol) in dioxane (5 mL) was heated to 100° C. for 12h. The reaction was cooled to RT, concentrated in vacuo, and extractedwith EtOAc. The combined organic layers were washed with brine, driedover Na₂SO₄, and concentrated in vacuo. Purification on normal phasesilica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(550 mg, 0.9 mmol) in acetonitrile (5 mL) was added TMSI (705 mg, 3.5mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h, thenconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (20 mL)followed by the sequential addition of Et₃N (267 mg, 2.6 mmol), and(BOC)₂O (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for16 h then concentrated in vacuo. Purification on normal phase silica gel(CH₂Cl₂/MeOH) provides (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as alight yellow solid.

Step 4:

A mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (350mg, 0.56 mmol),3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(285 mg, 1.1 mmol) and Pd(dppf)Cl₂ (62 mg, 0.09 mmol) in dioxane (5mL)/aq. Na₂CO₃ solution (2.0 M, 5 mL) was heated to 90° C. for 4 h. Thereaction was cooled to RT, the solids filtered away, and the solutionconcentrated in vacuo. Purification on normal phase silica gel(CH₂Cl₂/MeOH) provided (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a brown solid.

Step 5:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(150 mg, 0.19 mmol) in CH₂Cl₂ (5 mL) was added TFA (3 mL), and theresulting mixture was stirred at RT for 1 h. The reaction mixture wasconcentrated in vacuo, and the resulting material partitioned betweenCH₂Cl₂ and saturated NaHCO₃, and extracted. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification by prep-TLC (CH₂Cl₂/MeOH) provided (S)-ethyl8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas a brown solid.

Step 6:

To a solution of (S)-ethyl8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (70 mg, 0.11mmol) in MeOH (3 mL) is added 4 N NaOH (3 mL), and the reaction mixturewas stirred at RT for 4 h. The reaction mixture was then concentrated invacuo. The residue was diluted with water (5 mL) and the pH adjusted to6-7. The precipitated solid was collected by filtration, and the filtercake was washed with cold water, then dried to afford the title compoundas an off-white solid.

¹H NMR (400 MHz, DMSO-d6): δ ppm 7.72-7.70 (d, 1H), 7.61-7.59 (d, 3H),7.31-7.30 (d, 1H), 7.06-7.04 (d, 2H), 6.14 (s, 1H), 4.76 (s, 2H),3.87-3.83 (q, 1H), 3.46-3.41 (m, 4H), 3.08-3.06 (d, 1H), 2.98-2.95 (d,1H), 2.43 (s, 1H), 2.16-2.13 (m, 1H), 1.82-1.80 (m, 1H), 1.44 (m, 4H).LCMS (MH+): 514.

Example 62:(S)-8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid

Step 1:

A mixture of (2-bromo-4-chlorophenyl)methanol (173 mg, 1 mmol),4-chloro-6-(chloromethyl)pyrimidin-2-amine (178 mg, 1.16 mmol) and K₂CO₃(175 mg, 1.00 mmol) in DMF (5 mL) was heated to 100° C. for 12 h. Thereaction was cooled to RT, concentrated in vacuo, and extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated in vacuo. Purification on normal phase silicagel (EtOAc/petroleum ether) provided4-((2-bromo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine as a whitesolid.

Step 2:

A mixture of 4-((2-bromo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine(300 mg, 1.1 mmol), (S)-2-benzyl 3-ethyl2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (400 mg, 1.2 mmol), andNaHCO₃ (550 mg, 7 mmol) in dioxane (5 mL) was heated to 100° C. for 12h. The reaction was cooled to RT, concentrated in vacuo, and extractedwith EtOAc. The combined organic layers were washed with brine, water,dried over Na₂SO₄, and concentrated in vacuo. Purification on normalphase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a white solid.

Step 3:

To a solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(500 mg, 0.8 mmol) in acetonitrile (5 mL) was added TMSI (705 mg, 3.5mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2h, then concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (20mL), followed by the sequential addition of Et₃N (267 mg, 2.6 mmol), and(BOC)₂O (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for16 h, then concentrated in vacuo. Purification on normal phase silicagel (CH₂Cl₂/MeOH) provided (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas a light yellow solid.

Step 4:

A mixture of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg,0.4 mmol), (3-(methylsulfonyl)phenyl)boronic acid (280 mg, 1 mmol), andPd(dppf)Cl₂ (62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na₂CO₃ solution(2.0 M, 5 mL) was heated to 90° C. for 4 h. The reaction was then cooledto RT, the solids filtered away, and the filtrate concentrated in vacuo.Purification on normal phase silica gel (CH₂Cl₂/MeOH) provided(S)-2-tert-butyl 3-ethyl8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 5:

To a solution of (S)-2-tert-butyl 3-ethyl8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(200 mg, 0.25 mmol) in CH₂Cl₂ (5 ml) was added TFA (3 mL), and theresulting mixture was stirred at RT for 1 h. The reaction mixture wasconcentrated in vacuo, and the residue was partitioned between CH₂Cl₂and saturated NaHCO₃. The organic layer was dried over Na₂SO₄, filtered,and concentrated in vacuo. Purification by prep-TLC (CH₂Cl₂/MeOH)provided (S)-ethyl8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylateas an off-white solid.

Step 6:

To a solution (S)-ethyl8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(100 mg, 0.13 mmol) in MeOH (3 mL) was added 4 N NaOH (3 mL), and themixture was stirred at RT for 4 h. The reaction mixture was thenconcentrated in vacuo. The residue was diluted with water (5 mL) and thepH adjusted to 6-7. The precipitated solid was collected by filtration,the filter cake was washed with cold water, then dried to afford thetitle compound as an off-white solid isolated as the zwitterionic form.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.94 (m, 2H), 7.59-7.57 (m, 3H),7.44-7.40 (m, 1H), 7.33 (m, 1H), 5.33 (m, 1H), 4.07 (m, 1H), 3.59 (m,2H), 3.45 (m, 2H), 3.30 (m, 1H), 3.15 (m, 1H), 2.32 (m, 1H), 2.06 (m,1H), 1.61 (s, 4H). LCMS (MH+): 573.

The following esters were isolated as either a TFA or HCl salt formedduring the HPLC purification procedure used to isolate the finalcompounds.

Example 63bd: (S)-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

A solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(from Step 3, Example 1m, 220 mg, 0.3 mmol,) in EtOAc (5 mL) washydrogenated using Method A by using an H-Cube apparatus and a 10% (w/w)Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification onnormal phase silica gel (EtOAc/heptane) provided (S)-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate.

Example 63kp: (S)-ethyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

The title compound was prepared as described for (S)-ethyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 63bd) using Method A to remove the N-CBz group.

Example 63i: (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

A solution of (S)-2-benzyl 3-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(from Step 3, Example 34c, 315 mg, 0.43 mmol) in acetonitrile (300 mL)was added TMSI (0.13 mL, 0.9 mmol) [Method B]. The reaction mixture wasthen warmed to RT for an additional 30-40 min, then cooled to 0-5° C.,and 2 M HCl in diethyl ether (0.5 mL) was added. The reaction mixturewas the allowed to warm RT and then concentrated in vacuo. Normal phasesilica gel chromatography provide the title compound as an off-whitesolid.

Ethyl ester prodrugs in Table 18a were prepared by removing the N-CBZgroup by either method A or method B, as shown below.

TABLE 18a

Ex. Method LCMS No. Ar A or B CAS Name (MH+) 63a

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (benzo[d]thiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 613 63b

A (S)-ethyl 8-(6-((R)-1-(4-(1H- indazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate 596 63c

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methoxy-4′-(pyrrolidine-1-carbonyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 683 63d

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-nitro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 631 63e

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- (benzo[d]isothiazol-5-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 613 63f

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (benzo[d]isothiazol-6-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 616 63g

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 616 63h

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-methyl-2-oxo-1,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 637 63i

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 591 63j

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- amino-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 606 63k

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 676 63l

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (1,3-dimethyl-1H-indol-5-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 622 63m

A (S)-ethyl-8-(6-((R)-1-(3′- acrylamido-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate   659.1 63n

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-methoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 604 63o

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 587 63p

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 626 63q

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-oxo-1,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 623 63r

B (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 674 63s

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 585 63t

B (S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 671 64u

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 677 63v

B (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-4-((E)-prop-1-en-1-yl)-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 675 63w

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(ethylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 683 63x

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(propylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 697 63y

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(butylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 711 63z

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-oxo-1,3-dihydroisobenzofuran-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 612 63aa

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-methoxyquinolin-6-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 638 63ab

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(hydroxymethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 621 63ac

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(2-oxopyrrolidin-1-yl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 673 63ad

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(3-methyl-2-oxoimidazolidin-1-yl)-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimdin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate688 63ae

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 668 63af

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(methylsulfonamido)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 683 63ag

B (S)-ethyl 8-(2-amino-6-((R)-1-(2- bromo-5-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 593 63ah

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate ( 595 63ai

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-(methylthio)quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 554 63aj

B (S)-ethyl 8-(2-amino-6-((R)-1- (2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 638 63ak

A (S)-ethyl 8-(6-((R)-1-([1,1′:4′,1″- terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 633 63al

A (S)-ethyl 8-(2-amino-6-((R)-1-(2′- (ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 708 63am

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (ethoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 708 63an

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (ethoxycarbonyl)-3-(3-methyl]-1H-pyrazol-1-yl)-[1,1′-biphenyl- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 708 63ao

B (S)-ethyl 8-(2-amino-6-((R)-1- (2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 638 63ap

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 625 63aq

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 605 63ar

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 659 63as

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(methylthio)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 58363at

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 591 63au

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 651 63av

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 651 63aw

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 705 63ax

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2-oxopyrrolidin-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 598 63ay

B ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 594 63az

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 594 63ba

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 587 63bb

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-methoxy-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 591 63bc

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 575 63bd

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 665 63be

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 589 63bf

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4- propylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 603 63bg

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 617 63bh

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- (ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 633 63bi

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (ethoxycarbonyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 632 63bj

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- ((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 559 63bk

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- (3-ethoxy-3-oxopropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 588 63bl

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 618 63bm

B (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-((E)-prop-1-en-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 600 63bn

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 664 63bo

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5- propylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 602 63bp

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 588 63bq

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- butyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 616 63br

B (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5- vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 586 63bs

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- ((E)-but-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 614 63bt

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 594 63bu

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(1-methyl-1H-pyrazol-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 560 63bv

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (1,3-dimethyl-1H-indazol-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 624 63bw

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (2,3-dimethyl-2H-indazol-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 624 63bx

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 625 63by

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(isoquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 607 63bz

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (3-ethoxy-3-oxopropyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 660 63ca

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(isoquinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 607 63cb

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- (4-ethoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 674 63cc

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (4-ethoxy-4-oxobutyl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 594 63cd

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (4-ethoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 674 63ce

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- cyano-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 661 63cf

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-cyano-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 615 63cg

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 620 63ch

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 669 63ci

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-hydroxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 606 63cj

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 668 63ck

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (aminomethyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 619 63cl

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 608 63cm

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(quinolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 608 63cn

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 694 63co

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(quinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 608 63cp

A (S)-ethyl 8-(6-((R)-1-(4′- (acetamidomethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 707 63cq

A (S)-ethyl 8-(6-((R)-1-(4′-(2- acetamidoethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 721 63cr

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 687 63cs

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 666 63ct

A (S)-ethyl 8-(6-((R)-1-(4-(1H- indol-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 595 63cu

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 662 63cv

B 2′-((R)-1-((2-amino-6-((S)-3- (ethoxycarbonyl)-2,8-diazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)oxy)-2,2,2-trifluoroethyl)-5′-chloro-[1,1′- biphenyl]-3-carboxylic acid 634 63cw

B (S)-ethyl 8-(6-((R)-1-(3′- (acrylamidomethyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 673 63cx

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- carbamoyl-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 633 63cy

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 668 63cz

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 669 63da

A (S)-ethyl 8-(2-amino-6-((R)-1-(2′- (ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 708 63db

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 708 63dc

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 708 63dd

A (3S)-ethyl 8-(2-amino-6-((1R)-1- (4-(1,2-dihydroxyethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 620 63de

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (aminomethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 666 63df

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- ((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 734 63dg

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- ((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 734 63dh

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (3-ethoxy-3-oxopropyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 736 63di

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (3-ethoxy-3-oxopropyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 736 63dj

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 654 63dk

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 687 63dl

A (3S)-ethyl 8-(2-amino-6-((1R)- 2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(2-oxo-1,3- dioxolan-4-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 646 63dm

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 639 63dn

A (S)-ethyl 8-(6-((R)-1-(4- (acetamidomethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 631 63do

A (3S)-ethyl 8-(2-amino-6-((1R)- 2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-((2-((2- oxotetrahydrofuran-3-yl)thio)ethyl)carbamoyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 823 63dp

A (S)-ethyl 8-(2-amino-6-((R)-1- (3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″- terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 738 63dq

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(methylsulfonyl)-5-(quinolin-6-yl)-[1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 761 63dr

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(hydroxymethyl)-3′-methyl-4-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 68063ds

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-4-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 68063dt

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(methoxycarbonyl)-4-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 69463du

A 3′-((S)-1-((2-amino-6-((R)-3- (ethoxycarbonyl)-2,8-diazaspiro[4.5]decan-8- yl)pyrimidin-4-yl)oxy)-2,2,2-trifluoroethyl)-4′-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl-4-carboxylic acid 680 63dv

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-oxo-1,3- dihydroisobenzofuran-5-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 693 63dw

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(quinazolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 608 63dx

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 638 63dy

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 672 63dz

B (S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 671 63ea

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 591 63eb

B (S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 671 63ec

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-difluoro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 672 63ed

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 636 63ee

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dichloro-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-3- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 705 63ef

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin- 4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 574 63eg

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-(pyrimidin-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 638 63eh

B (S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 643 63ei

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 635 63ej

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-ethoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 669 63ek

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-5′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 643 63el

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 647 63em

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5″-dichloro-5′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 693 63en

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-5′-(trifluoromethyl)-[1,1′-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 677 63eo

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 591 63ep

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 621 63eq

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 649 63er

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dihcloro-4′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 639 63es

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 683 63et

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-4′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 667 63eu

B (S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 693 63ev

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 609 63ew

B (S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 639 63ex

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoromethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 693 63ey

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,5″-difluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 63ez

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-4′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 63fa

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,4′-difluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 63fb

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,4′-dimethyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 619 63fc

B (S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-3′,5′-dimethyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 653 63fd

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-ethoxy-3′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 653 63fe

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,5′-dimethyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 619 63ff

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5-dichloro-5′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 639 63fg

(S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 623 63fh

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-methyl-4′-(trifluoromethoxy)-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 689 63fi

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 675 63fj

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isopropyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 633 63fk

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 727 63fl

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 623 63fm

B (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′,5,5″-trichloro-[1,1′- biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 659 63fn

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-fluoro-3′-(trifluoromethyl)-[1,1′-biphenyl]- 2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 677 63fo

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyridin-3-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 592 63fp

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-fluoro-5′-isopropoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 667 63fq

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethoxy-5′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 653 63fr

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5-chloro-5′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 661 63fs

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-cyano-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 616 63ft

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- ethoxy-5′-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 698 63fv

B (S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 689 63fw

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 715 63fx

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 680 63fy

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5′-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 672 63fz

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3′-(trifluoromethyl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 70463ga

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethoxy-4′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 653 63gb

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-isopropoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 71263gc

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 664 63gd

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-5′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 685 63ge

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 678 63gf

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 692 63gg

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 671 63gh

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 689 63gi

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-difluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 672 63gj

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-3′- (trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate722 63gk

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- choro-3-(3-methyl-1H-pyrazol-1-yl)-5′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 739 63gl

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3′- (trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 720 63gm

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 706 63gn

B (S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 685 63go

B (S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3′,5′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 699 63gp

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-fluoro-3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 668 63gq

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 698 63gr

B (S)-ethyl 8-(2-amino-6-((R)-1- (3′,5′-dichloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 705 63gs

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-isopropyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 678 63gt

B (S)-ethyl 8-(2-amino-6-((R)-1-(4′- chloro-3-(3-methyl-1H-pyrazol-1-yl)-3′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 739 63gu

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-3-(3-methyl-1H-pyrazol-1-yl)-4′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 738 63gv

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- carbamoyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 679 63gw

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-3′,5′- bis(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 772 63gx

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 694 63gy

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- ethoxy-4′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 698 63gz

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-5′-isopropoxy-3-(3-methyl-1H- pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 71263ha

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 666 63hb

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 680 63hc

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′,4′,5′-trifluoro-3-(3- methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 690 63hd

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 622 63he

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-4′- (trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 734 63hf

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 685 63hg

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-5′- (trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate722 63hh

A (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-5′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 689 63hi

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-cyclopropyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 631 63hj

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- chloro-4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 729 63hk

B (S)-ethyl 8-(2-amino-6-((R)-1-(2- (benzo[d]thiazol-5-yl)-4-chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 648 63hl

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2-(dimethylamino)pyridin-4- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 635 63hm

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(naphthalen-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 641 63hn

B (S)-ethyl 8-(2-amino-6-((R)-1-(3′- (tert-butyl)-5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 647 63ho

B (S)-ethyl 8-(6-((R)-1-(2-(1H- benzo[d]imidazol-1-yl)-4-chlorophenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 631 63hp

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1H-indazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 631 63hq

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2-isopropylpyridin-4-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 634 63hr

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-fluoro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 609 63hs

B (S)-ethyl 8-(2-amino-6-((R)-1- (4′,5-dichloro-[1,1-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 625 63ht

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-4′-methyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 605 63hu

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(naphthalen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 687 63hv

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 595 63hw

A (S)-ethyl 8-(2-amino-((R)-1-(4′- (benzyloxy)-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoromethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 761 63hx

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isopropoxy-3′-methyl-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 70963hy

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isobutoxy-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 663 63hz

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 690 63ia

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-fluoroquinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 626 63ib

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 713 63ic

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- butoxy-3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 727 63id

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-4′-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 734 63ie

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 688 63if

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(cyclopentyloxy)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 675 63ig

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(morpholine-4-carbonyl)-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 704 63ih

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(((1R,4R)-4-hydroxycyclohexyl)carbamoyl)- [1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 732 63ii

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-ethyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 619 63ij

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-isopropyl-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 633 63ik

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 614 63il

A (S)-ethyl 8-(2-amino-6-((R)-1-(2- ethyl-4-(3-fluoroquinolin-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 654 63im

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(4-methylpiperazine-1-carbonyl)-[1,1′-biphenyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 717 63in

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(3-fluoroquinlin-6-yl)-2-methylphenyl)ethoxy) pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 640 63io

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (diethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 656 63ip

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- carbamoyl-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 600 63iq

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(2-methylthiazol-5-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 612 63ir

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-propoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 691 63is

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 631 63it

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 635 63iu

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(methylsulfonyl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 71563iv

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 695 63ix

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (diethylcarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 736 63iy

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(methylcarbamoyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 613 63iz

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-sulfamoyl-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 715 63ja

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-sulfamoyl-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 635 63jb

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-((2-morpholinoethoxy)carbamoyl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 712 63jc

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-((2- morpholinoethyl)carbamoyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 792 63jd

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 628 63je

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 669 63jf

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(piperazine-1- carbonyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 74963jg

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 622 63jh

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- (dimethylcarbamoyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]- 4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 708 63ji

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-methoxy-3-(3-methyl-1H-pyrazol-1-yl)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 68563jj

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-fluoro-4′-propoxy-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 633 63jk

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′- (methylcarbamoyl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 694 63jl

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(N-methylsulfamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 684 63jm

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(N,N-dimethylsulfamoyl)-[1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 698 63jn

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isopropoxy-3-morpholino-[1,1′-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 700 63jo

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(methylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 648 63jp

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(dimethylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 662 63jq

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-3′-fluoro-[1,1′-biphenyl]-4-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 618 63jr

A (S)-ethyl 8-(2-amino-6-((R)-1-(4′- ethoxy-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 601 63js

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 635 63jt

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(diethylcarbamoyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 690 63ju

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-isobutoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 709 63jv

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-4′-(neopentyloxy)- [1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 72363jw

B (S)-ethyl 8-(6-((R)-1-(2-(1H- benzo[d]imidazol-4-yl)-4-chlorophenyl)-2,2,2- trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 631 63jx

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (chroman-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 693 63jy

B (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 703 63jz

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(4-cyclopropylpiperazine-1- carbonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 743 63ka

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (cinnolin-6-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 689 63kb

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 649 63kc

B (S)-ethyl 8-(2-amino-6-((R)-1-(2- (3-(tert-butyl)-1H-pyrazol-1-yl)-4-chlorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 637 63kd

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 624 63ke

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 622 63kf

A (S)-ethyl 8-(2-amino-6-((R)-1- (3′,4′-dimethyl-3-(3-(trifluoromethyl)-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 719 63kg

A (S)-ethyl 8-(2-amino-6-((R)- 2,2,2-trifluoro-1-(3-fluoro-4-propoxy-[1,1′:3′,1″-terphenyl]-4′- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 660 63kh

A (S)-ethyl 8-(2-amino-6-((R)-1- (3,4-dimethyl-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 708 63ki

A (S)-ethyl 8-(6-((R)-1-([1,1′- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 556 63kj

A (S)-ethyl 8-(6-((R)-1-([1,1′:3′,1″- terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 633 63kl

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(hydroxymethyl)-4-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 667 63km

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (chroman-6-yl)phenyl)-2,2,2-trifuoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate612 63kn

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyridin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 592 63ko

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyrimidin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 593 63kp

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 68163kq

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4′-(hydroxymethyl)-3′-methyl-3-(3-methyl-1H-pyrazol-1- yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate 68163kr

A (S)-ethyl 8-(2-amino-6-((R)-1-(4- (6-ethoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 681 63ks

A (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-1-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-1H-pyrazol-1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 668 63kt

A (S)-ethyl 8-(2-amino-6-((R)-1-(5- chloro-3′-(2-methoxyethoxy)-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 665 63ku

B (S)-ethyl 8-(2-amino-6-((R)-1-(4- chloro-2-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 594 63kv

B (S)-ethyl 8-(2-amino-6-((S)-1- (3′,4′-bis(hydroxymethyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate 697

TABLE 18b NMR Data for Compounds of Table 18a Ex. No. NMR 63a ¹H NMR(400 MHz, MeOH-d4): δ PPM 1.26 (t, J = 7.1 Hz, 3H), 1.50 (m, 5H), 1.63(s, 1H), 1.73 (dd, J = 13.0, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.7 Hz,1H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.50 (pd, J =13.6, 5.4 Hz, 5H), 3.81 (t, J = 8.0 Hz, 1H), 4.17 (qd, J = 7.0, 1.6 Hz,2H), 4.92 (s, 6H), 5.55 (s, 1H), 6.66 (q, J = 7.2 Hz, 1H), 7.63 (d, J =8.0 Hz, 2H), 7.77 (m, 4H), 8.10 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 1.8Hz, 1H), 9.24 (s, 1H) 63b ¹H NMR (400 MHz, CDCl3): δ ppm 1.28 (m, 5H),1.59 (t, J = 5.6 Hz, 2H), 1.77 (dd, J = 13.1, 6.8 Hz, 1H), 2.09 (m, 1H),2.87 (d, J = 10.6 Hz, 1H), 2.98 (d, J = 10.6 Hz, 1H), 3.51 (dt, J =14.9, 5.0 Hz, 4H), 3.92 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.62 (s, 2H),5.54 (s, 1H), 6.63 (q, J = 7.0 Hz, 1H), 7.40 (dd, J = 8.5, 1.4 Hz, 1H),7.62 (q, J = 8.3 Hz, 6H), 7.81 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H) 63c ¹HNMR (400 MHz, CDCl3): δ ppm 0.87 (dd, J = 7.5, 3.2 Hz, 1H), 1.28 (dd, J= 14.0, 6.9 Hz, 7H), 1.57 (dt, J = 17.4, 5.6 Hz, 4H), 1.87 (m, 5H), 2.11(dd, J = 13.1, 8.8 Hz, 1H), 2.89 (d, J = 10.6 Hz, 1H), 2.99 (d, J = 10.6Hz, 1H), 3.28 (t, J = 6.7 Hz, 2H), 3.51 (m, 4H), 3.67 (t, J = 6.9 Hz,2H), 3.89 (s, 4H), 4.21 (q, J = 7.1 Hz, 2H), 4.59 (s, 2H), 5.53 (s, 1H),6.61 (q, J = 7.1 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.17 (dd, J = 7.7,1.5 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.58 (s, 4H) 63d ¹H-NMR (400 MHz,MeOH-d4): δ ppm 1.62 (m, 4H), 2.09-2.04 (m, 1H), 2.40-2.35 (m, 1H), 3.14(m, 1H), 3.25 (m, 1H), 3.47 (m, 2H), 3.31-3.30 (m, 2H), 4.22-4.20 (m,1H), 5.49 (s, 1H), 5.83-5.80 (m, 1H), 6.52-6.38 (m, 2H), 6.65 (m, 1H),7.31 (d, J = 2.0, 1H), 7.45-7.43 (d, J = 8.0, 3H), 7.68-7.66 (d, J =8.0, 1H), 7.80-7.78 (d, J = 8.0, 2H) 63e ¹H NMR (400 MHz, CDCl3): δ ppm0.07 (s, 1H), 0.87 (dd, J = 17.8, 8.8 Hz, 2H), 1.12 (s, 3H), 1.29 (m,18H), 1.51 (s, 1H), 1.63 (dq, J = 29.6, 7.7, 6.6 Hz, 10H), 1.89 (dd, J =13.2, 7.4 Hz, 2H), 2.23 (dd, J = 13.2, 8.6 Hz, 2H), 3.13 (m, 4H), 3.53(h, J = 6.6 Hz, 16H), 4.04 (s, 1H), 4.20 (dq, J = 33.0, 7.5 Hz, 8H),4.35 (s, 1H), 4.60 (m, 5H), 5.52 (d, J = 16.0 Hz, 2H), 6.64 (q, J = 7.0Hz, 2H), 7.39 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.65 (q, J = 7.9 Hz,9H), 7.79 (dd, J = 24.7, 8.0 Hz, 3H), 8.03 (d, J = 8.5 Hz, 2H), 8.23 (s,2H), 8.97 (s, 2H) 63f ¹H NMR (400 MHz, CDCl3): δ ppm 0.87 (dd, J = 16.5,9.8 Hz, 2H), 1.28 (m, 12H), 1.58 (m, 4H), 1.79 (dd, J = 13.1, 6.9 Hz,1H), 2.12 (dd, J = 13.1, 8.9 Hz, 1H), 2.90 (d, J = 10.7 Hz, 1H), 3.00(d, J = 10.6 Hz, 1H), 3.52 (dt, J = 11.4, 5.4 Hz, 7H), 3.96 (t, J = 7.8Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.61 (s, 2H), 5.54 (s, 1H), 6.64 (q,J = 7.1 Hz, 1H), 7.66 (q, J = 8.4 Hz, 5H), 8.12 (t, J = 4.2 Hz, 2H),8.94 (s, 1H) 63g ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (m, 4H), 1.64(dq, J = 14.1, 8.9, 7.2 Hz, 4H), 2.03 (td, J = 13.3, 8.9 Hz, 1H), 2.49(dd, J = 13.6, 8.7 Hz, 1H), 3.27 (s, 2H), 3.58 (m, 4H), 3.88 (d, J =11.8 Hz, 6H), 4.32 (qd, J = 7.2, 2.5 Hz, 2H), 4.58 (t, J = 8.8 Hz, 1H),6.62 (q, J = 7.1 Hz, 1H), 7.03 (m, 1H), 7.19 (m, 2H), 7.57 (d, J = 8.2Hz, 2H), 7.64 (m, 2H) 63h ¹H NMR (400 MHz, CDCl3): δ ppm 7.769-7.796 (m,1H), 7.707-7.740 (m, 2H), 7.585-7.636 (m, 4H), 7.422-7.444 (m, 1H),6.738-6.762 (m, 1H), 6.579-6.658-6.537 (m, 1H), 5.521 (s, 1H), 4.612 (s,2H), 4.200-4.253 (q, 2H), 4.114-4.154 (t, 1H), 3.747 (s, 3H),3.475-3.523 (m, 4H), 3.047-3.160 (m, 2H), 2.171-2.726 (m, 1H),1.840-1.891 (m, 1H), 1.543-1.649 (m, 4H), 1.209-1.305 (t, 3H) 63i ¹H NMR(400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.42-1.69 (m, 4 H)1.92 (dd, J = 13.25, 9.35 Hz, 1 H) 2.35 (dd, J = 13.25, 8.47 Hz, 1 H)3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J = 7.09, 2.10 Hz, 2 H)4.54 (br. s., 1 H) 5.77 (br. s., 1 H) 6.70 (q, J = 6.65 Hz, 1 H) 7.37(d, J = 2.10 Hz, 1 H) 7.43-7.52 (m, 3 H) 7.53-7.69 (m, 4 H) 9.23 (br.s., 1 H) 10.44 (br. s., 1 H) 63j ¹H NMR (400 MHz, CD3OD): δ ppm7.66-7.64 (d, 1 H, J = 8.6 Hz), 7.43-7.41 (d, 1 H, J = 8.6 Hz),7.26-7.20 (m, 2 H), 6.82-6.68 (m, 4 H), 5.42 (s, 1 H), 4.19-4.16 (q, 1H, J = 7.0 Hz), 3.83-3.81 (t, 1 H), 3.49-3.47 (m, 4 H), 2.91-2.89 (d, 1H, J = 10.9 Hz), 2.77-2.75 (d, 1 H, J = 10.9 Hz), 2.11-2.07 (m, 1 H),2.12-2.10 (m, 1 H), 1.53-1.51 (m, 4 H), 1.28-1.25 (t, 3 H, J = 7.0 HzHz) 63k ¹H NMR (400 MHz, MeOH-d4): δ ppm 8.42 (s, 1 H), 8.30 (d, 1 H),7.61 (m, 2 H), 7.31 (m, 1 H), 7.10 (s, 1 H), 6.58 (m, 1 H), 5.57 (s, 1H), 4.20 (m, 2 H), 3.84 (m, 1 H), 3.48 (m, 4 H), 3.16 (s, 3 H), 2.77 (m,1 H), 2.70 (m, 1 H), 2.61 (m, 1 H), 2.14 (m, 1 H), 1.77 (m, 1 H), 1.65(m, 2 H), 1.54 (m, 4 H), 1.20 (m, 3 H), 0.98 (m, 3 H) 63l ¹H NMR (400MHz, CD3OD-d4): δ ppm 1.28-1.24 (m, 4H), 7.72-7.68 (m, 3 H), 1.52 (m, 4H), 1.71 (m, 1 H), 2.10 (m, 1 H), 2.32 (s, 3 H), 2.76-2.73 (m, 1 H),2.90-2.87 (m, 1 H), 3.49 (m, 4 H), 3.75 (s, 3 H), 3.81 (m, 2 H),4.20-4.15 (m, 2 H), 5.54 (s.1H), 6.65-6.59 (m, 1 H), 6.93 (s, 1 H),7.37-7.34 (m, 1 H), 7.45-7.42 (m, 1 H), 7.57-7.55 (m, 2 H) 63m ¹H NMR(400 MHz, MeOH-d4): δ ppm 8.19 (s, 1 H), 7.64 (d, 1 H), 7.53-7.42 (m, 5H), 7.29 (s, 1 H), 7.16 (s, 2 H), 6.63 (q, 1 H), 6.52-6.35 (m, 3 H),5.80-5.77 (d, 1 H), 5.50 (s, 1 H), 4.21-4.18 (m, 2 H), 3.97 (t, 1 H),3.49 (m, 4 H), 2.98-2.95 (d, 1 H), 2.86-2.83 (d, 1 H), 2.16-2.14 (m, 1H), 1.80-1.76 (m, 1 H), 1.54 (m, 4 H), 1.19-1.16 (t, 3 H) 63n ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.27 (q, J = 7.1, 6.1 Hz, 4H), 1.52 (dt, J =10.4, 5.7 Hz, 4H), 1.74 (dd, J = 13.0, 7.2 Hz, 1H), 2.09 (dd, J = 13.1,8.8 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52(tq, J = 14.5, 8.2 Hz, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, 1H), 3.90 (s,3H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.89 (d, J = 1.5 Hz, 13H), 5.51 (d,J = 18.8 Hz, 2H), 6.62 (q, J = 7.1 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H),7.39 (m, 2H), 7.59 (m, 4H) 63o ¹H-NMR (400 MHz, MeOH-d4): δ ppm δ8.00(d, J = 2.36 Hz, 1H), 7.88 (dd, J = 2.6, 6.76 Hz, 1H), 7.58 (m, 4H),6.62 (m, 2H), 5.55 (s, 1H), 4.22 (m, 3H), 3.64 (s, 3H), 3.52 (m, 4H),3.02 (m, 2H), 2.27 (m, 1H), 1.89 (m, 1H), 1.59 (m, 4H), 1.29 (t, J =7.16 Hz, 3H). 63p ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.62 (d, 2H, J =8.0), 7.56 (d, 2H, J = 8.0), 7.45 (m, 2H), 6.93 (d, 1H, J = 8.0), 6.62(q, 1H, J = 8.0), 5.54 (s, 1H), 4.21 (t, 2H, J = 4.0), 3.99 (t, 1H, J =4.0), 3.56δ3.49 (m, 4H), 3.00 (dd, 3H, J = 20.0, 8.0), 2.86 (d, 1H, J =8.0), 2.59-2.57 (m, 2H), 2.18 (dd, 2H, J = 12.0, 8.0), 1.80 (dd, 2H, J =8.0, 4.0), 1.54 (m, 5), 1.28 (t, 4H, J = 8.0) 63q ¹H-NMR (400 MHz,CDCl3): δ ppm 11.76 (m, 1H), 7.84-7.86 (m, 1H), 7.70-7.73 (m, 2H), 7.59(m, 4H), 7.43-7.45 (m, 1H), 6.73-6.75 (m, 1H), 6.57-6.63 (q, 1H), 5.53(s, 1H), 4.61 (s, 2H), 4.17-4.23 (q, 2H), 3.90-3.94 (t, 1H), 3.48-3.51(m, 4H), 2.86-2.99 (m, 2H), 2.07-2.12 (m, 2H), 1.74-1.79 (m, 1H),1.53-1.59 (m, 4H), 1.24-1.29 (t, 3H). 63r ¹H NMR (400 MHz, CD3OD-d4): δppm 8.42 (s, 1 H), 8.04 (d, 1 H), 7.79 (m, 3 H), 7.63 (m, 1 H), 7.46 (m,1 H), 6.58 (m, 1 H), 6.40 (m, 1 H), 5.56 (m, 1 H), 4.18 (m, 2 H), 3.83(m, 1 H), 3.50 (m, 4 H), 3.21 (s, 3 H), 2.90 (m, 1 H), 2.78 (m, 1 H),2.14 (m, 1 H), 1.86 (m, 3 H), 1.76 (m, 1 H), 1.54 (m, 4 H), 1.26 (m, 3H) 63s ¹H NMR (MeOH-d4): δ ppm 0.90 (t, J = 6.9 Hz, 1H), 1.17 (p, J =6.3 Hz, 3H), 1.29 (s, 2H), 1.56 (m, 4H), 1.80 (s, 1H), 2.29 (s, 1H),2.41 (s, 3H), 2.80 (m, 4H), 3.26 (d, J = 11.3 Hz, 1H), 3.44 (s, 1H),4.09 (tdd, J = 14.2, 7.9, 4.6 Hz, 2H), 4.48 (s, 1H), 4.87 (s, 2H), 5.56(s, 1H), 6.42 (t, J = 2.2 Hz, 1H), 6.93 (m, 1H), 7.46 (m, 4H), 7.61 (m,2H), 7.80 (dd, J = 8.3, 2.2 Hz, 1H), 7.93 (dd, J = 5.2, 2.5 Hz, 2H) 63t¹H NMR (MeOH-d4): δ ppm 0.91 (dd, J = 12.4, 6.3 Hz, 2H), 1.17 (q, J =7.4 Hz, 3H), 1.31 (d, J = 16.3 Hz, 3H), 1.65 (m, 4H), 1.83 (s, 1H), 2.32(s, 2H), 2.41 (s, 3H), 2.92 (ddt, J = 18.2, 14.3, 9.1 Hz, 5H), 3.28 (s,1H), 4.11 (dtt, J = 10.7, 7.1, 3.9 Hz, 2H), 4.48 (s, 1H), 4.95 (d, J =11.7 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.94 (q, J = 6.5 Hz, 1H), 7.50(m, 3H), 7.61 (dd, J = 8.6, 2.1 Hz, 2H), 7.79 (dt, J = 8.3, 1.4 Hz, 1H),7.93 (dd, J = 10.2, 3.2 Hz, 2H) 63u ¹H NMR (400 MHz, CDCl₃-d): δ ppm8.50 (s, 1H), 7.99-7.96 (m, 1H), 7.69-7.63 (m, 2H), 7.51 (s, 1H),7.25-7.23 (m, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.57 (q, J = 6.6 Hz, 1H),5.51 (s, 1H), 5.18 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.93-3.89 (m, 1H),3.53-3.48 (m, 4H), 3.14 (s, 3H), 2.93 (dd, J1 = 10.6 Hz, J2 = 42.0 Hz,2H), 2.66-2.62 (m, 2H), 2.12-2.07 (m, 1H), 1.79-1.74 (m, 1H), 1.69-1.63(m, 2H), 1.61-1.58 (m, 2H), 1.55-1.52 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H),0.95 (t, J = 7.3 Hz, 3H) 63v ¹H NMR (400 MHz, CDCl₃): δ ppm 8.52 (d, J =9.5 Hz, 1H), 7.99-7.97 (m, 1H), 7.69-7.62 (m, 3H), 7.38 (dd, J1 = 7.9Hz, J2 = 20.6 Hz, 1H), 7.15 (dd, J1 = 7.9 Hz, J2 = 17.0 Hz, 1H), 6.57(m, 1H), 6.46-6.42 (m, 1H), 6.34-5.84 (m, 1H), 5.51-5.50 (m, 1H), 5.18(s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.87 (t, J = 7.6 Hz, 1H), 3.52-3.50(m, 4H), 3.15-3.14 (m, 3H), 2.90 (dd, J1 = 10.2 Hz, J2 = 47.8 Hz, 2H),2.10-2.05 (m, 1H), 1.91 (d, J = 6.4 Hz, 3H), 1.78-1.73 (m, 1H),1.58-1.53 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H) 63w ¹H NMR (400 MHz,MeOH-d4): δ ppm 8.49 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 7.8Hz, 1H), 7.65-7.63 (m, 2H), 7.42-7.40 (m, 1H), 7.23 (d, J = 1.9 Hz, 1H),6.53 (q, J = 6.8 Hz, 1H), 5.48 (s, 1H), 5.26 (s, 2H), 4.22 (q, J = 7.1Hz, 2H), 4.03 (t, J = 8.0 Hz, 1H), 3.52-3.51 (m, 4H), 3.21 (q, J = 7.4Hz, 2H), 3.02 (dd, J1 = 10.9 Hz, J2 = 34.9 Hz, 2H), 2.18-2.12 (m, 1H),1.85-1.80 (m, 1H), 1.62-1.61 (m, 2H), 1.56-1.55 (m, 2H), 1.31-1.28 (m,6H) 63x 1H NMR (400 MHz, MeOH-d4): δ ppm 8.45 (s, 1H), 8.03 (d, 1H, J =8.0), 7.83 (t, 1H, J = 8.0), 7.79-7.69 (m, 2H), 7.50 (d, 1H, J = 8.0),7.37 (s, 1H), 6.62 (q, 1H, J = 8.0), 5.61 (s, 1H), 4.38 (t, 1H, J =8.0), 4.32-4.27 (m, 2H), 3.64-3.49 (m, 4H), 3.16 (q, 2H, J = 12.0), 2.39(dd, 1H, J = 12.0, 8.0), 1.98 (dd, 1H, J = 12.0, 8.0), 1.70-1.62 (m,7H), 1.31 (dd, 5H, J = 12.0, 8.0) 0.96 (t, 4H, J = 8.0) 63y ¹H NMR (400MHz, MeOH-d4): δ ppm 8.50 (s, 1 H), 8.05-8.03 (d, 1 H), 7.82 (t, 1 H),7.76-7.70 (m, 2 H), 7.52-7.51 (d, 1 H), 7.38-7.37 (d, 1 H), 6.62-6.60(q, 1 H), 5.60 (s, 1 H), 4.20-4.19 (q, 2 H), 3.85 (t, 1 H), 3.57 (m, 4H), 2.82 (d, 1 H), 2.77 (d, 1 H), 2.09 (m, 1 H), 1.77 (m, 1 H), 1.57 (m,6 H), 1.31 (q, 2 H), 1.26 (m, 3 H), 0.84-0.81 (t, 3 H) 63z ¹H NMR (400MHz, MeOH-d4): δ ppm 0.09 (dd, J = 4.2, 2.0 Hz, 1H), 0.90 (t, J = 6.5Hz, 3H), 1.28 (m, 14H), 1.54 (dt, J = 10.5, 5.6 Hz, 6H), 1.76 (dd, J =13.2, 7.3 Hz, 1H), 2.03 (s, 1H), 2.15 (ddd, J = 29.1, 14.1, 8.4 Hz, 2H),2.78 (d, J = 10.9 Hz, 1H), 2.92 (d, J = 11.0 Hz, 1H), 3.53 (td, J =13.8, 13.4, 6.0 Hz, 6H), 3.86 (dd, J = 8.8, 7.3 Hz, 1H), 4.20 (m, 3H),5.46 (d, J = 22.4 Hz, 3H), 5.56 (s, 1H), 6.67 (q, J = 7.2 Hz, 2H), 7.66(d, J = 8.1 Hz, 3H), 7.75 (m, 3H), 7.85 (m, 3H), 7.93 (d, J = 7.9 Hz,2H) 63aa ¹H NMR (400 MHz, MeOH-d4): δ ppm: 8.16 (d, J = 8.84 Hz, 1H),8.03 (d, J = 1.84 Hz, 1H), 7.94-7.81 (m, 2H), 7.77 (d, J = 8.32 Hz, 2H),7.64 (d, J = 8.24 Hz, 2H), 6.96 (d, J = 8.88 Hz, 1H), 6.65 (q, J = 7.08Hz, 1H), 5.56 (s, 1H), 4.18 (m, 2H), 4.06 (s, 3H), 3.82 (m, 1H), 3.53(m, 4H), 2.90 (d, J = 11.0 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.09 (m,1H), 1.75 (m, 1H), 1.53 (s, 4H), 1.27 (t, J = 7.12 Hz, 3H) 63ab ¹H NMR(400 MHz, CDCl3): δ ppm 7.76 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.43 (t,J = 7.6 Hz, 1H), 7.37 (dd, J1 = 2.2 Hz, J2 = 8.5 Hz, 1H), 7.33 (d, J =7.6 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.63(q, J = 6.7 Hz, 1H), 5.41 (s, 1H), 5.02 (s, 2H), 4.80 (m, 2H), 4.21 (q,J = 7.1 Hz, 2H), 4.05-4.01 (m, 1H), 3.48-3.46 (m, 4H), 3.01 (dd, J1 =10.9 Hz, J2 = 31.0 Hz, 2H), 2.17-2.11 (m, 1H), 1.83-1.78 (m, 1H),1.59-1.50 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H) 63ac ¹H-NMR (400 MHz,MeOH-d4): δ ppm 7.97 (s, 1H), 7.60-7.67 (m, 2H), 7.52-7.56 (m, 1H),7.43-7.45 (m, 1H), 7.31-7.31 (m, 1H), 7.22-7.24 (m, 1H), 6.621-6.663 (m,1H), 5.498 (s, 1H), 4.16-4.22 (m, 2H), 4.92-4.03 (m, 2H), 3.83-3.87 (m,1h), 3.46-3.53 (m, 4H), 2.90-2.92 (d, 1H), 2.76-2.78 (d, 1H), 2.59-2.63(m, 2H), 2.10-2.22 (m, 3H), 1.71-1.78 (m, 1H), 1.52-1.55 (m, 4H),1.25-1.28 (m, 3H) 63ad ¹H-NMR (400 MHz, MeOH-d4) δ ppm: 7.98 (s, 1H),7.63-7.65 (m, 1H), 7.42-7.50 (m, 3H), 7.30-7.30 (m, 1H), 7.05-7.07 (m,1H), 6.62-6.67 (m, 1H), 5.49 (s, 1H), 4.15-4.22 (m, 2H), 3.80-3.98 (m,3H), 3.46-3.56 (m, 6h), 2.73-2.92 (m, 4H), 2.73-2.78 (d, 1H), 2.07-2.13(d, 1H), 1.73-1.78 (m, 1H), 1.49-1.57 (m, 4H), 1.25-1.29 (m, 3H) 63ae ¹HNMR (400 MHz, DMSO-d6) δ ppm: 1.25 (t, J = 7.10 Hz, 3 H) 1.42-1.69 (m, 4H) 1.92 (dd, J = 13.25, 9.35 Hz, 1 H) 2.35 (dd, J = 13.25, 8.47 Hz, 1 H)3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J = 7.09, 2.10 Hz, 2 H)4.54 (br. s., 1 H) 5.77 (br. s., 1 H) 6.70 (q, J = 6.65 Hz, 1 H) 7.37(d, J = 2.10 Hz, 1 H) 7.43-7.52 (m, 3 H) 7.53-7.69 (m, 4 H) 9.23 (br.s., 1 H) 10.44 (br. s., 1 H) 63af ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.66(d, 1 H, J = 8.4 Hz), 7.50 (m, 3 H), 7.31 (d, 2 H, J = 8.7 Hz), 7.24 (d,1 H, J = 7.2 Hz), 6.64 (m, 1 H), 5.50 (m, 1 H), 4.21 (m, 1 H), 3.87 (m,1 H), 3.53 (m, 4 H), 3.01 (s, 3 H), 3.18 (m, 1 H), 2.90 (m, 3 H), 2.79(m, 1 H), 2.07 (m, 1 H), 1.74 (m, 1 H), 1.53 (m, 4 H), 1.27 (m, 3 H)63ag ¹H NMR (400 MHz, CDCl3): δ ppm 7.54 (d, J = 2.2 Hz, 1H), 7.51 (d, J= 8.6 Hz, 1H), 7.19 (dd, J1 = 2.6 Hz, J2 = 8.6 Hz, 1H), 6.85 (q, J = 6.6Hz, 1H), 5.49 (s, 1H), 4.56 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.90-3.86(m, 1H), 3.53-3.47 (m, 4H), 2.90 (dd, J1 = 10.4 Hz, J2 = 47.6 Hz, 2H),2.13-2.05 (m, 1H), 1.78-1.73 (m, 1H), 1.59-1.56 (m, 2H), 1.54-1.51 (m,2H), 1.28 (t, J = 7.1 Hz, 3H) 63ah ¹H NMR (400 MHz, CDCl3): δ ppm 7.54(d, J = 2.2 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.19 (dd, J1 = 2.6 Hz, J2= 8.6 Hz, 1H), 6.85 (q, J = 6.6 Hz, 1H), 5.49 (s, 1H), 4.56 (s, 2H),4.20 (q, J = 7.2 Hz, 2H), 3.90-3.86 (m, 1H), 3.53-3.47 (m, 4H), 2.90(dd, J1 = 10.4 Hz, J2 = 47.6 Hz, 2H), 2.13-2.05 (m, 1H), 1.78-1.73 (m,1H), 1.59-1.56 (m, 2H), 1.54-1.51 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H) 63ai¹H NMR (400 MHz, MeOH-d4): δ ppm 8.06 (d, J = 8.72 Hz, 1H), 8.01 (s,1H), 7.94 (s, 2H), 7.76 (d, J = 8.28 Hz, 2H), 7.64 (d, J = 8.16 Hz, 2H),7.31 (d, J = 8.68 Hz, 1H), 6.66 (q, J = 7.32 Hz, 1H), 5.56 (s, 1H), 4.18(q, J = 7.04 Hz, 2H), 3.84-3.80 (m, 1H), 3.51 (m, 4H), 2.89 (d, J =10.96 Hz, 1H), 2.75 (d, J = 11 Hz, 1H), 2.68 (s, 3H), 2.10-2.01 (m, 1H),1.76-1.71 (m, 1H), 1.54-1.49 (m, 4H), 1.25 (t, J = 7.12 Hz, 3H) 63aj ¹HNMR (400 MHz, MeOH-d4): δ ppm 7.69 (d, J = 1.8 Hz, 1H), 7.60-7.57 (d,1H), 7.48 (dd, J1 = 2.44, J2 = 8.6 Hz, 1H), 6.96 (q, J = 7.32 Hz, 1H),5.56 (s, 1H), 4.19 (q, J = 7.12 Hz, 2H), 3.86-3.82 (m, 1H), 3.54 (m,4H), 2.91 (d, J = 11 Hz, 1H), 2.77 (d, J = 11 Hz, 1H), 2.14-2.08 (m,1H), 1.79-1.73 (m, 1H), 1.55 (m, 4H), 1.27 (t, J = 7.12 Hz, 3H) 63ak ¹HNMR (400 MHz, MeOH-d4): δ ppm 7.91 (s, 1H), 7.71 (dd, J1 = 6.12 Hz, J2 =1.96 Hz, 1H), 7.63 (m, 2H), 7.56-7.49 (m, 7H), 7.39-7.35 (m, 2H), 6.74(q, J = 6.88 Hz, 1H), 5.50 (s, 1H), 4.18 (q, J = 6.96 Hz, 2H), 3.83 (m,1H), 3.50 (m, 4H), 2.89 (d, J = 11.04 Hz, 1H), 2.75 (d, J = 11 Hz, 1H),2.12-2.06 (m, 1H), 1.76-1.71 (m, 1H), 1.54-1.49 (m, 4H), 1.27 (t, J =7.12 Hz, 3H) 63al ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.84 (t, J = 7.1 Hz,8H), 1.26 (t, J = 7.1 Hz, 8H), 1.50 (dt, J = 11.1, 5.8 Hz, 4H), 1.73(dd, J = 13.1, 7.1 Hz, 1H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.38 (s,3H), 2.73 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.51 (m, 4H),3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.00 (qd, J = 7.1, 4.5 Hz, 2H), 4.17(qd, J = 7.1, 1.5 Hz, 2H), 5.74 (s, 1H), 6.39 (d, J = 2.3 Hz, 1H), 6.85(q, J = 6.7 Hz, 1H), 7.45 (m, 5H), 7.80 (m, 2H), 7.90 (d, J = 2.4 Hz,1H) 63am ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 1.26 (m, 7H),1.40 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H),2.05 (m, 1H), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0Hz, 1H), 3.53 (m, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.18 (qd, J =7.1, 2.5 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J =2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.68(d, J = 1.9 Hz, 1H), 7.79 (m, 2H), 7.90 (dt, J = 8.0, 1.4 Hz, 1H), 8.02(m, 2H), 8.28 (d, J = 1.9 Hz, 1H) 63an ¹H NMR (400 MHz, MeOH-d4): δ ppm1.33 (dt, J = 54.3, 7.1 Hz, 6H), 1.50 (dt, J = 10.8, 5.8 Hz, 4H), 1.73(dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s,3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H),3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 4.38 (q,J = 7.1 Hz, 2H), 5.74 (s, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.84 (q, J =6.6 Hz, 1H), 7.77 (m, 5H), 8.00 (d, J = 2.3 Hz, 1H), 8.09 (m, 2H) 63ao¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.54 (m, 4H),1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, 1H), 2.77(dd, J = 11.0, 1.1 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.53 (td, J =11.9, 11.4, 4.9 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J =7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.27 (q, J =8.0 Hz, 1H), 7.69 (m, 2H) 63ap ¹H NMR (400 MHz, CDCl3): δ ppm 1.28 (m,4H), 1.56 (dq, J = 25.2, 5.5, 4.9 Hz, 4H), 1.78 (dd, J = 13.1, 6.9 Hz,1H), 2.12 (m, 1H), 2.90 (d, J = 10.7 Hz, 1H), 2.99 (d, J = 10.6 Hz, 1H),3.49 (dt, J = 11.5, 5.7 Hz, 4H), 3.94 (dd, J = 8.8, 6.9 Hz, 1H), 4.21(q, J = 7.1 Hz, 2H), 4.58 (s, 2H), 5.43 (s, 1H), 6.55 (q, J = 6.8 Hz,1H), 7.24 (m, 3H), 7.41 (m, 3H), 7.65 (m, 2H) 63aq ¹H NMR (400 MHz,CDCl3): δ ppm 0.84 (m, 2H), 1.14 (s, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.53(m, 4H), 1.74 (dd, J = 13.1, 6.8 Hz, 1H), 2.05 (m, 1H), 2.43 (s, 3H),2.82 (d, J = 10.5 Hz, 1H), 2.94 (d, J = 10.5 Hz, 1H), 3.46 (dt, J =14.0, 5.8 Hz, 4H), 3.86 (dd, J = 8.8, 6.7 Hz, 1H), 4.19 (q, J = 7.1 Hz,2H), 4.35 (s, 2H), 5.40 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H), 7.33 (m, 5H),7.65 (d, J = 8.5 Hz, 1H) 63ar ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t,J = 7.1 Hz, 4H), 1.54 (dt, J = 7.9, 4.7 Hz, 4H), 1.76 (dd, J = 13.1, 7.2Hz, 1H), 2.12 (m, 1H), 2.78 (m, 1H), 2.90 (m, 1H), 3.52 (m, 4H), 3.85(td, J = 9.2, 8.8, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.86 (d,J = 0.8 Hz, 11H), 5.51 (d, J = 13.8 Hz, 1H), 6.52 (q, J = 6.7 Hz, 1H),7.34 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.75 (m, 5H)63as ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.1 Hz, 3H), 1.67 (m,4H), 2.05 (dd, J = 13.6, 8.8 Hz, 1H), 2.46 (d, J = 45.5 Hz, 7H), 2.66(s, 1H), 3.28 (s, 2H), 3.69 (m, 4H), 4.32 (qd, J = 7.1, 2.3 Hz, 2H),4.58 (t, J = 8.7 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.85 (q, J = 6.3 Hz,1H), 7.37 (m, 2H), 7.66 (m, 3H), 7.79 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H)63at ¹H NMR (MeOH-d4): δ ppm 1.28 (m, 15H), 1.53 (m, 13H), 1.76 (dd, J =13.1, 7.3 Hz, 3H), 1.86 (s, 1H), 2.12 (dd, J = 13.1, 8.8 Hz, 3H), 2.79(d, J = 11.0 Hz, 3H), 2.92 (d, J = 11.0 Hz, 3H), 3.51 (qdt, J = 18.0,13.3, 5.9 Hz, 12H), 3.63 (d, J = 8.6 Hz, 1H), 3.87 (m, 3H), 4.19 (qd, J= 7.1, 1.6 Hz, 5H), 5.51 (s, 3H), 6.68 (q, J = 6.7 Hz, 3H), 7.29 (m,6H), 7.47 (m, 19H), 7.65 (m, 5H) 63au ¹H NMR (MeOH-d4): δ ppm 1.13 (s,2H), 1.26 (t, J = 7.3 Hz, 4H), 1.49 (m, 6H), 1.73 (dd, J = 13.1, 7.2 Hz,1H), 2.06 (dd, J = 13.1, 8.7 Hz, 1H), 2.38 (d, J = 12.1 Hz, 7H), 2.73(d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H), 3.53 (tt, J = 14.1, 5.1Hz, 5H), 3.81 (m, 1H), 4.18 (tt, J = 7.8, 3.6 Hz, 2H), 4.81 (s, 2H),4.97 (d, J = 15.9 Hz, 1H), 5.74 (s, 1H), 6.41 (d, J = 2.1 Hz, 1H), 6.78(q, J = 6.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 7.57 (m, 5H), 7.73 (m,2H), 7.96 (d, J = 2.3 Hz, 1H) 63av ¹H NMR (MeOH-d4): δ ppm 1.26 (m, 3H),1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.07(dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 7H), 2.74 (d, J = 10.9 Hz, 1H),2.88 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H),4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H),6.79 (q, J = 6.6 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.6 Hz,1H), 7.46 (m, 2H), 7.62 (d, J = 1.9 Hz, 1H), 7.75 (m, 2H), 7.98 (d, J =2.4 Hz, 1H) 63aw ¹H NMR (MeOH-d4): δ ppm 0.90 (m, 1H), 1.27 (m, 5H),1.51 (dt, J = 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09(dd, J = 13.1, 8.7 Hz, 1H), 2.40 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H),2.90 (d, J = 11.0 Hz, 1H), 3.54 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H),4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H),6.84 (q, J = 6.5 Hz, 1H), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4Hz, 1H) 63ax ¹H NMR (400 MHz, Chloroform-d): δ ppm 1.27 (m, 9H), 1.52(dt, J = 22.3, 5.4 Hz, 4H), 1.72 (d, J = 13.1 Hz, 1H), 2.05 (m, 1H),2.25 (ddd, J = 18.1, 13.9, 8.2 Hz, 2H), 2.63 (m, 2H), 2.82 (d, J = 10.5Hz, 1H), 2.94 (d, J = 10.4 Hz, 1H), 3.48 (dd, J = 13.6, 7.4 Hz, 5H),3.63 (m, 1H), 3.81 (m, 4H), 4.19 (q, J = 7.1 Hz, 2H), 4.86 (s, 2H), 5.46(s, 1H), 6.46 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.5, 2.2Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H) 63ay ¹H NMR (400 MHz, MeOH-d4): δ ppm1.35 (d, J = 2.64 Hz, 4 H) 1.61-1.86 (m, 5 H) 2.04-2.16 (m, 1 H) 2.42(d, J = 1.27 Hz, 3 H) 2.48-2.60 (m, 1 H) 3.55-4.03 (m, 4 H) 4.25-4.44(m, 2 H) 4.55-4.70 (m, 1 H) 6.45 (s, 1 H) 6.90-7.04 (m, 1 H) 7.61 (s, 2H) 7.68-7.79 (m, 1 H) 7.88-8.00 (m, 1 H) 63az ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.25 (t, J = 7.15 Hz, 3 H) 1.43-1.60 (m, 4 H) 1.78 (dd, J = 13.13,7.42 Hz, 1 H) 2.13 (dd, J = 13.08, 8.74 Hz, 1 H) 2.35 (s, 3 H) 2.73-3.01(m, 2 H) 3.39-3.63 (m, 4 H) 3.94 (t, J = 7.91 Hz, 1 H) 4.18 (qd, J =7.13, 1.78 Hz, 2 H) 5.65 (s, 1 H) 6.38 (d, J = 2.39 Hz, 1 H) 6.79 (q, J= 6.74 Hz, 1 H) 7.41-7.54 (m, 2 H) 7.68 (d, J = 8.35 Hz, 1 H) 7.91 (d, J= 2.34 Hz, 1 H) 63ba ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 7.13Hz, 3 H), 1.53-1.75 (m, 4 H), 2.05 (dd, J = 13.62, 8.88 Hz, 1 H), 2.49(dd, J = 13.57, 8.74 Hz, 1 H), 3.27 (s, 2 H), 3.42-3.74 (m, 4 H), 3.84(s, 3 H), 4.25-4.40 (m, 2 H), 4.58 (t, J = 8.79 Hz, 1 H), 5.60 (s, 1 H),6.59-6.71 (m, 1 H), 6.92 (ddd, J = 8.22, 2.54, 0.76 Hz, 1 H), 7.11-7.16(m, 1 H), 7.16-7.24 (m, 1 H), 7.31-7.38 (m, 1 H), 7.54-7.61 (m, 2 H),7.62-7.70 (m, 2 H) 63bb ¹H NMR (400 MHz, dichloromethane-d2): δ ppm 1.29(t, J = 7.15 Hz, 3 H) 1.47-1.85 (m, 4 H) 2.01 (dd, J = 13.52, 8.30 Hz, 1H) 2.30-2.36 (m, 1 H) 2.38 (s, 3 H) 3.27-3.41 (m, 2 H) 3.41-3.67 (m, 4H) 3.82 (s, 3 H) 4.26 (qd, J = 7.17, 4.00 Hz, 2 H) 4.45 (t, J = 8.49 Hz,1 H) 4.96 (br. s, 2H) 5.49 (s, 1 H) 6.31 (d, J = 2.25 Hz, 1 H) 6.62 (q,J = 6.90 Hz, 1 H) 6.88 (d, J = 2.59 Hz, 1 H) 6.96 (dd, J = 8.81, 2.61Hz, 1 H) 7.61 (d, J = 8.74 Hz, 1 H) 7.66 (d, J = 2.25 Hz, 1 H) 63bc ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.22 Hz, 3 H) 1.67-1.89 (m, 4H) 2.05-2.18 (m, 1 H) 2.49-2.62 (m, 1 H) 3.56-3.90 (m, 4 H) 4.35 (dd, J= 7.13, 1.85 Hz, 2 H) 4.65 (s, 1 H) 5.97 (s, 1 H) 6.58-6.72 (m, 1 H)7.14 (br. s., 1 H) 7.41 (d, J = 9.18 Hz, 1 H) 7.45-7.53 (m, 2 H)7.64-7.72 (m, 2 H) 7.73-7.82 (m, 2 H) 63bd ¹H NMR (400 MHz, MeOH-d4): δppm 1.28-1.39 (m, 4 H) 1.74 (d, J = 18.35 Hz, 4 H) 2.03-2.14 (m, 1 H)2.35 (d, J = 12.89 Hz, 6 H) 2.43 (s, 3 H) 2.46-2.57 (m, 1 H) 3.62-3.96(m, 4 H) 4.34 (dd, J = 7.13, 1.85 Hz, 2 H) 4.56-4.68 (m, 1 H) 6.44 (d, J= 2.34 Hz, 1 H) 6.50-6.61 (m, 1 H) 6.81-6.96 (m, 1 H) 7.26 (d, J = 7.81Hz, 1 H) 7.40-7.47 (m, 1 H) 7.50 (s, 1 H) 7.68 (d, J = 1.37 Hz, 1 H)7.78 (s, 1 H) 7.82 (d, J = 1.37 Hz, 1 H) 7.98; (d, J = 2.15 Hz, 1 H)63be ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 6 H) 1.59 (m, 4 H) 2.02(m, 1 H) 2.38 (s, 3 H) 2.45 (dd, J = 13.54, 8.76 Hz, 1 H) 2.72 (q, J =7.60 Hz, 2 H) 3.24 (m, 2 H) 3.58 (m, 4 H) 4.32 (m, 2 H) 4.53 (t, J =8.76 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J = 2.20 Hz, 1 H) 6.71 (m, 1 H)7.25 (d, J = 1.56 Hz, 1 H) 7.36 (dd, J = 8.10, 1.61 Hz, 1 H) 7.63 (d, J= 8.10 Hz, 1 H) 7.85 (d, J = 2.29 Hz, 1 H) 63bf ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.96 (t, J = 7.35 Hz, 2 H) 1.32 (t, J = 7.15 Hz, 4 H)1.63 (m, 6 H) 2.00 (dd, J = 13.59, 8.61 Hz, 1 H) 2.37 (s, 3 H) 2.42 (m,1 H) 2.66 (m, 2 H) 3.21 (m, 2 H) 3.58 (m, 4 H) 4.31 (m, 2 H) 4.49 (t, J= 8.69 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J = 2.29 Hz, 1 H) 6.71 (q, J =6.67 Hz, 1 H) 7.23 (d, J = 1.66 Hz, 1 H) 7.34 (dd, J = 8.10, 1.66 Hz, 1H) 7.63 (d, J = 8.10 Hz, 1 H) 7.85 (d, J = 2.29 Hz, 1 H) 63bg ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.95 (t, J = 7.35 Hz, 3 H) 1.32 (t, J = 7.15Hz, 4 H) 1.63 (m, 6 H) 2.02 (m, 1 H) 2.38 (s, 3 H) 2.45 (dd, J = 13.54,8.76 Hz, 1 H) 2.69 (m, 2 H) 3.24 (m, 2 H) 3.58 (m, 4 H) 4.32 (m, 2 H)4.53 (t, J = 8.74 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J = 2.29 Hz, 1 H) 6.71(m, 1 H) 7.23 (d, J = 1.61 Hz, 1 H) 7.34 (dd, J = 8.15, 1.61 Hz, 1 H)7.62 (d, J = 8.15 Hz, 1 H) 7.85 (d, J = 2.34 Hz, 1 H) 63bh ¹H NMR (400MHz, CHLOROFORM-d): δ ppm 1.18-1.36 (m, 3 H) 1.43 (t, J = 6.74 Hz, 3 H)1.54-2.29 (m, 6 H) 2.39 (br. s., 3 H) 3.78 (br. s., 4 H) 4.26 (br. s., 2H) 4.42 (d J = 6.15 Hz, 2 H) 5.53 (br. s., 1 H) 6.36 (s, 1 H) 6.59 (br.s., 1 H) 7.48 (d, J = 7.96 Hz, 1 H)7.61 (br. s., 1 H) 8.16 (d, J = 8.05Hz, 1 H) 8.34 (br. s., 1 H) 63bi ¹H NMR (400 MHz, MeOH-d4): δ ppm1.24-1.30 (m, 5 H) 1.37 (t, J = 7.13 Hz, 3 H) 1.45-1.62 (m, 4 H) 1.84(dd, J = 13.32, 7.86 Hz, 1 H) 1.95 (s, 4 H) 2.22 (dd, J = 13.30, 8.86Hz, 1 H) 2.38 (s, 3 H) 2.88-3.09 (m, 2 H) 3.41-3.71 (m, 4 H) 4.10 (t, J= 8.25 Hz, 1 H) 4.22 (qd, J = 7.13, 2.00 Hz, 2 H) 4.37 (q, J = 7.13 Hz,2 H) 5.66 (s, 1 H) 6.41 (d, J = 2.39 Hz, 1 H) 6.84 (q, J = 6.54 Hz, 1 H)7.83 (d, J = 8.30 Hz, 1 H) 7.94 (d, J = 2.34 Hz, 1 H) 7.99 (d, J = 1.61Hz, 1 H) 8.08 (dd, J = 8.27, 1.64 Hz, 1 H) 63bj ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.31 (td, J = 7.13, 3.22 Hz, 6 H) 1.52-1.64 (m, 4 H)1.97 (s, 1 H) 2.01 (dd, J = 13.59, 8.81 Hz, 1 H) 2.37 (s, 3 H) 2.44 (dd,J = 13.62, 8.74 Hz, 1 H) 3.18-3.26 (m, 2 H) 3.43-3.68 (m, 4 H) 4.19-4.34(m, 4 H) 4.53 (t, J = 8.74 Hz, 1 H) 5.75 (s, 1 H) 6.40 (d, J = 2.39 Hz,1 H) 6.55 (d, J = 16.06 Hz, 1 H) 6.95 (q, J = 6.56 Hz, 1 H) 7.46 (d, J =8.30 Hz, 1 H) 7.68 (d, J = 16.06 Hz, 1 H) 7.80 (dd, J = 8.32, 2.03 Hz, 1H) 7.87 (s, 1 H) 7.91 (d, J = 2.39 Hz, 1 H) 63bk ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.92 (t, J = 7.37 Hz, 3 H) 1.32 (dq, J = 14.94, 7.38 Hz,2 H) 1.50-1.68 (m, 6 H) 2.06 (dd, J = 13.37, 7.22 Hz, 1 H) 2.31 (dd, J =13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.69 (t, J = 7.59 Hz, 2 H) 3.06-3.29(m, 2 H) 3.41-3.76 (m, 4 H) 4.08 (dd, J = 9.20, 7.25 Hz, 1 H) 5.75 (s, 1H) 6.36 (d, J = 2.15 Hz, 1 H) 6.69 (q, J = 6.62 Hz, 1 H) 7.28-7.33 (m, 1H) 7.34-7.39 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J = 2.29 Hz, 1 H) 63bl ¹HNMR (400 MHz, DMSO-d6): δ ppm 1.50-1.73 (m, 4 H) 1.80 (quin, J = 7.52Hz, 2 H) 1.90 (dd, J = 13.23, 9.22 Hz, 1 H) 2.15-2.26 (m, 2 H) 2.27-2.41(m, 4 H) 2.69 (t, J = 7.66 Hz, 2 H) 3.00-3.20 (m, 2 H) 3.69 (br. s., 4H) 4.33-4.52 (m, 1 H) 6.14 (br. s., 1 H) 6.38 (d, J = 2.29 Hz, 1 H) 7.05(br. s., 1 H) 7.37-7.52 (m, 3 H) 7.76 (br. s., 1 H) 8.02 (d, J = 2.29Hz, 1 H) 8.97 (d, J = 5.32 Hz, 1 H) 10.42 (br. s., 1 H) 63bm ¹H NMR (400MHz, MeOH-d4): δ ppm 1.31 (t, J = 7.15 Hz, 3 H) 1.52-1.70 (m, 4 H) 1.90(dd, J = 6.30, 1.22 Hz, 3 H) 1.97 (dd, J = 13.52, 8.44 Hz, 1 H)2.35-2.41 (m, 4 H) 3.06-3.24 (m, 2 H) 3.42-3.79 (m, 4 H) 4.21-4.35 (m, 2H) 4.40 (t, J = 8.57 Hz, 1 H) 5.75 (s, 1 H) 6.27-6.54 (m, 3 H) 6.75 (q,J = 6.64 Hz, 1 H) 7.32 (d, J = 8.25 Hz, 1 H) 7.52 (dd, J = 8.30, 2.00Hz, 1 H) 7.64 (s, 1 H) 7.83 (d, J = 2.29 Hz, 1 H) 63bn ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.32 (t, J = 7.15 Hz, 3 H) 1.49-1.70 (m, 4 H) 2.01 (dd,J = 13.59, 8.76 Hz, 1 H) 2.29 (s, 3 H) 2.32 (s, 3 H) 2.40 (s, 3 H)2.40-2.44 (m, 1 H) 3.24 (s, 2 H) 3.43-3.71 (m, 4 H) 4.22-4.41 (m, 2 H)4.56 (t, J = 8.74 Hz, 1 H) 5.80 (s, 1 H) 6.41 (d, J = 2.29 Hz, 1 H)6.81-6.92 (m, 1 H) 7.20 (d, J = 7.81 Hz, 1 H) 7.26-7.32 (m, 1 H) 7.35(s, 1 H) 7.45 (d, J = 8.30 Hz, 1 H) 7.73 (dd, J = 8.27, 2.12 Hz, 1 H)7.88-7.90 (m, 2 H) 63bo ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.92 (t, J =7.35 Hz, 3 H) 1.32 (t, J = 7.13 Hz, 3 H) 1.49-1.76 (m, 6 H) 1.94-2.06(m, 1 H) 2.37 (s, 3 H) 2.43 (dd, J = 13.57, 8.79 Hz, 1 H) 2.66 (t, J =7.52 Hz, 2 H)3.13-3.28 (m, 2 H) 3.43-3.76 (m, 4 H) 4.21-4.39 (m, 2 H)4.50 (t, J = 8.66 Hz, 1 H) 5.74 (s, 1 H) 6.37 (d, J = 2.29 Hz, 1 H) 6.70(q, J = 6.69 Hz, 1 H) 7.26-7.33 (m, 1 H) 7.34-7.42 (m, 1 H) 7.53 (s, 1H) 7.82 (d, J = 2.29 Hz, 1 H) 63bp ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25(t, J = 7.61 Hz, 3 H) 1.33 (t, J = 7.15 Hz, 3 H) 1.57-1.71 (m, 4 H) 2.04(dd, J = 13.93, 8.52 Hz, 1 H) 2.37 (s, 3 H) 2.47 (dd, J = 13.62, 8.74Hz, 1 H) 2.72 (q, J = 7.61 Hz, 2 H) 3.26 (d, J = 1.51 Hz, 2 H) 3.44-3.77(m, 4 H) 4.23-4.43 (m, 2 H) 4.57 (t, J = 8.79 Hz, 1 H) 5.76 (s, 1 H)6.37 (d, J = 2.20 Hz, 1 H) 6.63-6.78 (m, 1 H) 7.27-7.35 (m, 1 H)7.36-7.46 (m, 1 H) 7.55 (s, 1 H) 7.81 (d, J = 2.29 Hz, 1 H) 63bq ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.92 (t, J = 7.35 Hz, 3 H) 1.22-1.42 (m, 5 H)1.49-1.75 (m, 6 H) 1.94-2.08 (m, 1 H) 2.37 (s, 3 H) 2.44 (dd, J = 13.57,8.74 Hz, 1 H) 2.68 (t, J = 7.61 Hz, 2 H) 3.15-3.29 (m, 2 H) 3.42-3.76(m, 4 H) 4.23-4.40 (m, 2 H) 4.53 (t, J = 8.74 Hz, 1 H) 5.75 (s, 1 H)6.37 (d, J = 2.34 Hz, 1 H) 6.70 (q, J = 6.69 Hz, 1 H) 7.27-7.33 (m, 1 H)7.34-7.41 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J = 2.34 Hz, 1 H) 63br ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 7.13 Hz, 3 H) 1.53-1.74 (m, 4 H)2.05 (dd, J = 13.62, 8.83 Hz, 1 H) 2.38 (s, 3 H) 2.48 (dd, J = 13.62,8.79 Hz, 1 H) 3.28 (s, 2 H) 3.44-3.79 (m, 4 H) 4.22-4.43 (m, 2 H) 4.59(t, J = 8.79 Hz, 1 H) 5.37 (d, J = 11.08 Hz, 1 H) 5.73-5.96 (m, 2 H)6.39 (d, J = 2.34 Hz, 1 H) 6.68-6.95 (m, 2 H) 7.40 (d, J = 8.25 Hz, 1 H)7.65 (dd, J = 8.27, 1.98 Hz, 1 H) 7.73 (s, 1 H) 7.87 (d, J = 2.34 Hz, 1H) 63bs ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.11 (t, J = 7.47 Hz, 3 H) 1.33(t, J = 7.15 Hz, 3 H) 1.51-1.72 (m, 4 H) 2.04 (dd, J = 13.62, 8.83 Hz, 1H) 2.18-2.33 (m, 2 H) 2.38 (s, 3 H) 2.47 (dd, J = 13.59, 8.81 Hz, 1 H)3.26 (s, 2 H) 3.44-3.78 (m, 4 H) 4.19-4.43 (m, 2 H) 4.58 (t, J = 8.79Hz, 1 H) 5.79 (s, 1 H) 6.30-6.53 (m, 3 H) 6.69-6.84 (m, 1 H) 7.33 (d, J= 8.25 Hz, 1 H) 7.55 (dd, J = 8.30, 2.00 Hz, 1 H) 7.65 (s, 1 H) 7.84 (d,J = 2.34 Hz, 1 H) 63bt ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (t, J =7.13 Hz, 3 H) 1.45-1.65 (m, 4 H) 1.79-1.91 (m, 1 H) 2.16-2.32 (m, 1 H)3.03 (s, 2 H) 3.51 (br. s., 4 H) 3.75-3.81 (m, 1 H) 4.07-4.17 (m, 1 H)4.20-4.32 (m, 2 H) 5.55 (s, 1 H) 6.65 (d, J = 2.34 Hz, 1 H) 7.15-7.28(m, 1 H) 7.36-7.46 (m, 1 H) 7.57 (d, J = 2.15 Hz, 1 H) 7.62-7.70 (m, 1H) 7.73 (d, J = 2.15 Hz, 1 H) 63bu ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29(t, J = 7.13 Hz, 3 H) 1.40-1.61 (m, 4 H) 1.71-1.86 (m, 1 H) 2.07-2.22(m, 1 H) 2.86 (s, 1 H) 2.94 (s, 1 H) 3.50 (d, J = 4.69 Hz, 4 H) 4.00 (s,4 H) 4.22 (dd, J = 7.22, 0.98 Hz, 2 H) 5.57 (s, 1 H) 6.61 (d, J = 2.15Hz, 1 H) 7.13-7.28 (m, 1 H) 7.35-7.50 (m, 2 H) 7.55 (d, J = 1.17 Hz, 1H) 7.72 (d, J = 2.34 Hz, 2 H) 63bv ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35(t, J = 7.13 Hz, 3 H) 1.57-1.83 (m, 4 H) 1.99-2.16 (m, 1 H) 2.56 (s, 4H) 3.31 (s, 2 H) 3.68 (br. s., 4 H) 4.03 (s, 3 H) 4.35 (dd, J = 7.03,2.15 Hz, 2 H) 4.62 (s, 1 H) 5.70 (s, 1 H) 6.70 (d, J = 6.83 Hz, 1 H)7.42 (dd, J = 8.49, 0.88 Hz, 1 H) 7.60-7.72 (m, 3 H) 7.73-7.86 (m, 3 H)63bw ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 3 H)1.67-1.90 (m, 4 H) 2.03-2.18 (m, 1 H) 2.47-2.61 (m, 1 H) 2.72 (s, 3 H)3.34 (br. s., 2 H) 3.56-3.87 (m, 4 H) 4.17 (s, 3 H) 4.35 (dd, J = 7.13,2.05 Hz, 2 H) 4.64 (s, 1 H) 5.89-6.04 (m, 1 H) 6.59-6.75 (m, 1 H) 7.45(d, J = 0.98 Hz, 1 H) 7.70 (d, J = 8.20 Hz, 2 H) 7.77 (s, 1 H) 7.79-7.92(m, 3 H) 63bx ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 3H) 1.77 (br. s., 4 H) 2.04-2.15 (m, 1 H) 2.47-2.58 (m, 1 H) 3.09 (s, 2H) 3.57 (t, J = 6.74 Hz, 6 H) 4.28-4.43 (m, 2 H) 4.57-4.69 (m, 1H)5.80-5.92 (m, 1 H) 6.60-6.75 (m, 1 H) 7.62 (s, 1 H) 7.69 (d, J = 8.40Hz, 3 H) 7.74-7.85 (m, 2 H) 8.03 (d, J = 8.00 Hz, 1 H) 63by ¹H NMR (400MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 3 H) 1.61-1.81 (m, 4 H)2.00-2.16 (m, 1 H) 2.44-2.59 (m, 1 H) 3.47-3.80 (m, 4 H) 4.35 (dd, J =7.03, 2.54 Hz, 2 H) 4.63 (s, 1 H) 5.73 (s, 1 H) 6.64-6.83 (m, 1 H) 7.76(d, J = 8.20 Hz, 2 H) 7.95 (d, J = 8.20 Hz, 2 H) 8.12-8.33 (m, 2 H)8.36-8.47 (m, 2 H) 8.48-8.68 (m, 1 H) 9.39-9.76 (m, 1 H) 63bz ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.10-1.20 (m, 3 H) 1.26 (t, J = 7.13 Hz, 3 H)1.42-1.64 (m, 4 H) 1.79 (dd, J = 13.15, 7.44 Hz, 1 H) 1.94 (s, 2 H) 2.15(dd, J = 12.98, 8.69 Hz, 1 H) 2.35 (s, 3 H) 2.62-2.71 (m, 2 H) 2.81-2.87(m, 1 H) 2.93-3.02 (m, 3 H) 3.40-3.66 (m, 4 H) 3.96 (t, J = 8.18 Hz, 1H) 4.06 (q, J = 7.18 Hz, 2 H) 4.16-4.25 (m, 2 H) 5.69 (s, 1 H) 6.36 (d,J = 2.25 Hz, 1 H) 6.71 (q, J = 6.67 Hz, 1 H) 7.27 (d, J = 1.56 Hz, 1 H)7.35 (dd, J = 8.13, 1.83 Hz, 1 H) 7.62 (d, J = 8.20 Hz, 1 H) 7.83 (d, J= 2.29 Hz, 1 H) 63ca ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.13Hz, 3 H) 1.63-1.82 (m, 4 H) 2.03-2.17 (m, 1 H) 2.47-2.60 (m, 1 H)3.51-3.83 (m, 4 H) 4.27-4.42 (m, 2 H) 4.57-4.69 (m, 1 H) 5.69-5.88 (m, 1H) 6.65-6.85 (m, 1 H) 7.71-7.85 (m, 2 H) 7.89-8.01 (m, 2 H) 8.22-8.35(m, 2 H) 8.36-8.49 (m, 1 H) 8.52-8.60 (m, 1 H) 8.62-8.72 (m, 1 H)9.56-9.75 (m, 1 H) 63cb ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.18 (t, J =7.10 Hz, 3 H) 1.24 (t, J = 7.13 Hz, 3 H) 1.37-1.63 (m, 4 H) 1.82 (quin,J = 7.52 Hz, 2 H) 1.90 (dd, J = 13.28, 9.42 Hz, 1 H) 2.19-2.41 (m, 6 H)2.67 (t, J = 7.69 Hz, 2 H) 3.12 (br. s., 2 H) 3.18-3.74 (m, 4 H) 4.05(q, J = 7.13 Hz, 2 H) 4.15-4.30 (m, 2 H) 4.52 (t, J = 8.49 Hz, 1 H) 5.72(br. s., 1 H) 6.01 (br. s., 2 H) 6.37 (d, J = 2.15 Hz, 1 H) 6.99 (q, J =6.87 Hz, 1 H) 7.33-7.44 (m, 2 H) 7.47 (s, 1 H) 8.01 (d, J = 2.25 Hz, 1H) 9.20 (br. s., 1 H) 10.39 (br. s., 1 H) 63cc ¹H NMR (400 MHz,DMSO-d6): δ ppm 1.10-1.20 (m, 3 H) 1.25 (t, J = 7.10 Hz, 3 H) 1.44-1.63(m, 4 H) 1.82 (quin, J = 7.53 Hz, 2 H) 1.91 (dd, J = 13.28, 9.37 Hz, 1H) 2.19-2.40 (m, 3 H) 2.60 (t, J = 7.71 Hz, 2 H) 3.13 (br. s., 2 H)3.40-3.68 (m, 4 H) 4.02 (q, J = 7.09 Hz, 2 H) 4.13-4.33 (m, 2 H) 4.53(br. s., 1 H) 5.70 (br. s., 1 H) 6.29 (br. s, 2 H) 6.62-6.76 (m, 1 H)7.28 (d, J = 8.20 Hz, 2 H) 7.43 (d, J = 8.10 Hz, 2 H) 9.21 (br. s., 1 H)10.43 (br. s., 1 H) 63cd ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.15 (t, J =7.13 Hz, 3 H) 1.24 (t, J = 7.10 Hz, 3 H) 1.39-1.64 (m, 4 H) 1.78-1.97(m, 3 H) 2.22-2.39 (m, 6 H) 2.66 (t, J = 7.71 Hz, 2 H) 3.11 (br. s., 2H) 3.38-3.64 (m, 4 H) 3.93-4.07 (m, 2 H) 4.15-4.31 (m, 2 H) 4.52 (br.s., 1 H) 5.73 (br. s., 1 H) 6.05 (br. s., 2 H) 6.38 (d, J = 2.10 Hz, 1H) 7.00 (q, J = 6.72 Hz, 1 H) 7.30 (d, J = 1.51 Hz, 1 H) 7.33-7.41 (m, 1H) 7.59 (d, J = 8.05 Hz, 1 H) 8.04 (d, J = 2.29 Hz, 1 H) 9.20 (br. s., 1H) 10.38 (br. s., 1 H) 63ce ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.22-1.30(m, 3 H) 1.48-1.61 (m, 4 H) 1.82 (dd, J = 13.30, 7.74 Hz, 1 H) 1.94 (s,3 H) 2.15-2.23 (m, 1 H) 2.38 (s, 3 H) 2.87-2.92 (m, 1 H) 2.96-3.02 (m, 1H) 3.42-3.64 (m, 4 H) 4.01-4.08 (m, 1 H) 4.16-4.25 (m, 2 H) 5.72 (s, 1H) 6.41 (d, J = 2.39 Hz, 1 H) 6.81-6.88 (m, 1 H) 7.61-7.66 (m, 1 H) 7.71(d, J = 1.76 Hz, 1 H) 7.73-7.86 (m, 3 H) 7.97-8.02 (m, 2 H) 8.08 (s, 1H) 63cf ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.13 Hz, 3 H)1.45-1.66 (m, 4 H) 1.92 (dd, J = 13.18, 9.42 Hz, 1 H) 2.35 (dd, J =13.28, 8.54 Hz, 1 H) 3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.14-4.31 (m,2H) 4.54 (br. s., 1 H) 5.75 (br. s., 1 H) 6.56 (q, J = 6.72 Hz, 1 H)7.47 (t, J = 1.27 Hz, 1 H) 7.65 (s, 2 H) 7.75-7.84 (m, 1 H) 7.89 (d, J =7.81 Hz, 1 H) 7.93-8.01 (m, 2 H) 9.21 (br. s., 1 H) 10.36 (br. s., 1 H)63cg ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.57(d, J = 5.37 Hz, 4 H) 1.83-1.99 (m, 1 H) 2.28-2.40 (m, 1 H) 3.14 (br.s., 2 H) 3.58 (br. s., 4 H) 3.81 (s, 3 H) 4.24 (dd, J = 7.13, 2.25 Hz, 2H) 4.43-4.63 (m, 1 H) 5.62-5.85 (m, 1 H) 6.73 (d, J = 6.78 Hz, 1 H)6.96-7.16 (m, 3 H) 7.39 (d, J = 2.15 Hz, 1 H) 7.50 (dd, J = 8.74, 7.61Hz, 1 H) 7.55-7.69 (m, 2 H) 9.09-9.32 (m, 1 H) 10.26-10.47 (m, 1 H) 63ch¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.15 Hz, 3 H) 1.52-1.70(m, 4 H) 1.93-2.02 (m, 1 H) 2.40 (dd, J = 13.45, 8.71 Hz, 1 H) 3.09-3.24(m, 2 H) 3.43-3.74 (m, 4 H) 4.25-4.35 (m, 2 H) 4.40 (t, J = 8.57 Hz, 1H) 5.59 (s, 1 H) 6.61 (q, J = 6.56 Hz, 1 H) 7.32 (d, J = 2.15 Hz, 1 H)7.49 (dd, J = 8.49, 2.25 Hz, 1 H) 7.61 (d, J = 8.00 Hz, 1 H) 7.65-7.77(m, 2 H) 7.97-8.10 (m, 1 H) 8.32 (br. s., 1 H) 63ci ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.32 (t, J = 7.13 Hz, 3 H) 1.50-1.70 (m, 4 H) 1.91-2.02(m, 1 H) 2.39 (dd, J = 13.50, 8.76 Hz, 1 H) 3.08-3.23 (m, 2 H) 3.41-3.69(m, 4 H) 4.24-4.34 (m, 2 H) 4.38 (t, J = 8.54 Hz, 1 H) 5.50 (s, 1 H)6.75 (q, J = 6.96 Hz, 1 H) 6.87 (d, J = 7.66 Hz, 1 H) 6.91 (ddd, J =8.21, 2.50, 0.90 Hz, 1 H) 7.06 (br. s., 1 H) 7.28 (d, J = 2.20 Hz, 1 H)7.32 (t, J = 7.88 Hz, 1 H) 7.43 (dd, J = 8.47, 2.27 Hz, 1 H) 7.66 (d, J= 8.44 Hz, 1 H) 63cj ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.13Hz, 3 H) 1.52-1.70 (m, 4 H) 1.93-2.06 (m, 1 H) 2.41 (dd, J = 13.42, 8.74Hz, 1 H) 3.10-3.25 (m, 5 H) 3.44-3.74 (m, 4 H) 4.21-4.37 (m, 2 H) 4.42(t, J = 8.59 Hz, 1 H) 5.61 (s, 1 H) 6.57 (q, J = 6.57 Hz, 1 H) 7.36 (d,J = 2.20 Hz, 1 H) 7.51 (dd, J = 8.54, 2.20 Hz, 1 H) 7.70 (d, J = 8.44Hz, 1 H) 7.72-7.78 (m, 1 H) 7.78-7.89 (m, 1 H) 8.09 (dt, J = 7.85, 1.49Hz, 1 H) 8.41 (d, J = 0.73 Hz, 1 H) 63ck ¹H NMR (400 MHz, DMSO-d6): δppm 1.21 (t, J = 7.10 Hz, 3 H) 1.38-1.64 (m, 4 H) 1.88 (dd, J = 13.20,9.35 Hz, 1 H) 2.30 (dd, J = 13.20, 8.47 Hz, 1 H) 3.09 (br. s., 2 H)3.42-3.61 (m, 4 H) 3.95-4.11 (m, 2 H) 4.12-4.28 (m, 2 H) 4.48 (br. s., 1H) 5.71 (br. s., 1 H) 6.32 (br. s., 1 H) 6.71 (q, J = 6.74 Hz, 1 H) 7.33(d, J = 2.05 Hz, 1 H) 7.44-7.69 (m, 6 H) 8.52 (br. s., 3 H) 9.27 (br.s., 1 H) 10.62 (br. s., 1 H) 63cl ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35(t, J = 7.13 Hz, 4 H) 1.82 (br. s., 4 H) 2.03-2.21 (m, 1 H) 2.47-2.64(m, 1 H) 3.35 (s, 2 H) 3.56-3.92 (m, 4 H) 4.27-4.43 (m, 2 H) 4.59-4.70(m, 1 H) 6.65-6.82 (m, 1 H) 7.81 (d, J = 8.00 Hz, 2 H) 8.00 (d, J = 8.20Hz, 2 H) 8.05-8.14 (m, 1 H) 8.29-8.40 (m, 1 H) 8.46-8.55 (m, 1 H) 8.63(d, J = 1.56 Hz, 1 H) 9.21 (s, 2 H) 63cm ¹H NMR (400 MHz, MeOH-d4): δppm 1.35 (t, J = 6.93 Hz, 5 H) 1.83 (br. s., 4 H) 2.04-2.22 (m, 1 H)2.47-2.65 (m, 1 H) 3.36 (br. s., 2 H) 4.35 (d, J = 6.64 Hz, 2 H)4.57-4.71 (m, 1 H) 6.64-6.85 (m, 1 H) 7.84 (d, J = 6.64 Hz, 2 H) 8.03(d, J = 6.83 Hz, 2 H) 8.08-8.18 (m, 1 H) 8.27-8.41 (m, 1 H) 8.50 (br.s., 2 H) 9.26 (br. s., 2 H) 63cn ¹H NMR (400 MHz, MeOH-d4): δ ppm1.24-1.45 (m, 10 H) 1.75 (d, J = 18.55 Hz, 4 H) 2.01-2.18 (m, 1 H) 2.43(s, 3 H) 2.47-2.62 (m, 1 H) 3.86 (br. s., 3 H) 4.34 (d, J = 5.86 Hz, 2H) 4.54-4.75 (m, 2 H) 6.44 (d, J = 1.95 Hz, 1 H) 6.89 (d, J = 5.66 Hz, 1H) 7.03 (d, J = 8.59 Hz, 2 H) 7.57-7.71 (m, 3 H) 7.72-7.87 (m, 2 H) 7.98(d, J = 1.76 Hz, 1 H) 63co ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (s, 3H) 1.64-1.91 (m, 4 H) 2.03-2.20 (m, 1 H) 2.47-2.64 (m, 1 H) 3.35 (br.s., 2 H) 3.56-3.95 (m, 4 H) 4.25-4.44 (m, 2 H) 4.57-4.71 (m, 1 H)6.57-6.84 (m, 1 H) 7.70-7.85 (m, 2 H) 7.90-8.07 (m, 2 H) 8.23 (s, 2 H)8.33-8.47 (m, 1 H) 8.86-9.05 (m, 2 H) 63cp ¹H NMR (400 MHz, MeOH-d4): δppm 1.18-1.31 (m, 3 H) 1.44-1.60 (m, 4 H) 1.79 (dd, J = 13.28, 7.61 Hz,1 H) 1.93 (s, 2 H) 1.98 (s, 3 H)2.14 (dd, J = 13.18, 8.79 Hz, 1 H) 2.37(s, 3 H) 2.80-2.89 (m, 1 H) 2.91-3.00 (m, 1 H) 3.40-3.64 (m, 4 H) 3.97(t, J = 8.15 Hz, 1 H) 4.19 (qd, J = 7.13, 1.81 Hz, 2 H) 4.37 (s, 2 H)5.72 (s, 1 H) 6.39 (d, J = 2.20 Hz, 1 H) 6.76 (q, J = 6.56 Hz, 1 H) 7.36(d, J = 8.30 Hz, 2 H) 7.59-7.66 (m, 3 H) 7.69-7.81 (m, 2 H) 7.95 (d, J =2.29 Hz, 1 H) 63cq ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.10-1.20 (m, 3 H)1.25 (t, J = 7.10 Hz, 3 H) 1.44-1.63 (m, 4 H) 1H NMR (400 MHz, MeOH-d4):δ ppm 1.21-1.31 (m, 3 H) 1.52 (dt, J = 10.53, 5.35 Hz, 4 H) 1.79 (dd, J= 13.15, 7.44 Hz, 1 H) 1.89 (s, 3 H) 1.93 (s, 2 H) 2.14 (dd, J = 13.13,8.79 Hz, 1 H) 2.38 (s, 3 H) 2.78-2.88 (m, 3 H) 2.91-2.99 (m, 1 H) 3.40(t, J = 7.35 Hz, 2 H) 3.44-3.66 (m, 4 H) 3.95 (t, J = 8.13 Hz, 1 H)4.12-4.25 (m, 2 H) 5.72 (s, 1 H) 6.40 (d, J = 2.29 Hz, 1 H) 6.77 (q, J =6.74 Hz, 1 H) 7.31 (d, J = 8.25 Hz, 2 H) 7.58-7.64 (m, 3 H) 7.70-7.80(m, 2 H) 7.95 (d, J = 2.29 Hz, 1 H) 63cr ¹H NMR (400 MHz, MeOH-d4): δppm 1.25 (t, J = 7.13 Hz, 3 H) 1.47-1.58 (m, 4 H) 1.79 (dd, J = 13.20,7.44 Hz, 1 H) 1.93 (s, 2 H) 2.15 (dd, J = 13.23, 8.74 Hz, 1 H) 2.40 (s,3 H) 2.81-2.87 (m, 1 H) 2.92-2.98 (m, 1 H) 3.44-3.63 (m, 4 H) 3.97 (dd,J = 8.52, 7.83 Hz, 1 H) 4.14-4.24 (m, 2 H) 5.75 (s, 1 H) 6.42 (d, J =2.29 Hz, 1 H) 6.84 (q, J = 6.69 Hz, 1 H) 7.55 (dd, J = 8.30, 4.34 Hz, 1H) 7.83 (d, J = 1.76 Hz, 1 H) 7.85-7.99 (m, 3 H) 8.00-8.07 (m, 2 H) 8.30(d, J = 1.51 Hz, 1 H) 8.37-8.42 (m, 1 H) 8.88 (dd, J = 4.30, 1.66 Hz, 1H) 63cs ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.34 (d, J = 6.05 Hz, 6 H) 1.60(br. s., 4 H) 2.02-2.13 (m, 1 H) 2.26-2.37 (m, 1 H) 2.42 (s, 3 H)3.04-3.18 (m, 1 H) 3.26 (d, J = 11.71 Hz, 1 H) 3.41-3.78 (m, 4 H)4.02-4.17 (m, 1 H) 4.66 (s, 1 H) 5.78 (s, 1 H) 6.43 (d, J = 2.15 Hz, 1H) 6.69-6.86 (m, 1 H) 6.99 (d, J = 8.79 Hz, 2 H) 7.50-7.66 (m, 3 H)7.67-7.82 (m, 2 H) 7.97 (d, J = 2.34 Hz, 1 H) 63ct ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 3 H) 1.58-1.78 (m, 4 H) 2.02-2.16(m, 1 H) 2.43-2.60 (m, 1 H) 3.30 (s, 2 H) 3.46-3.78 (m, 4 H) 4.27-4.41(m, 2 H) 4.55-4.66 (m, 1 H), 5.61-5.77 (m, 1 H) 6.42-6.53 (m, 1 H)6.59-6.70 (m, 1 H) 7.25-7.39 (m, 2 H) 7.62 (s, 4 H) 7.72 (s, 2 H) 63cu¹H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.33 (t, J =7.10 Hz, 3 H) 1.44-1.64 (m, 4 H) 1.92 (dd, J = 13.28, 9.27 Hz, 1 H) 2.35(dd, J = 13.28, 8.49 Hz, 1 H) 3.14 (br. s., 2 H) 3.44-3.66 (m, 4 H)4.14-4.29 (m, 2 H) 4.30-4.43 (m, 2 H) 4.54 (br. s., 1 H) 5.75 (br. s., 1H) 6.43 (br. s., 1 H) 6.59 (q, J = 6.72 Hz, 1 H) 7.37-7.47 (m, 1 H)7.57-7.67 (m, 2 H) 7.68-7.81 (m, 2 H) 8.08 (dt, J = 6.77, 1.96 Hz, 1 H)8.24 (br. s., 1 H) 9.22 (br. s., 1 H) 10.41 (br. s, 1 H) 63cv ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.34 (t, J = 7.13 Hz, 3 H) 1.69-1.88 (m, 4 H)2.11 (dd, J = 13.64, 8.96 Hz, 1 H) 2.55 (dd, J = 13.62, 8.69 Hz, 1 H)3.34 (s, 2 H) 3.52-3.80 (m, 4 H) 4.35 (qd, J = 7.13, 1.93 Hz, 2 H) 4.63(t, J = 8.79 Hz, 1 H) 6.55-6.67 (m, 1 H) 7.37 (d, J = 2.20 Hz, 1 H) 7.54(dd, J = 8.52, 2.22 Hz, 1 H) 7.58-7.63 (m, 1 H) 7.65-7.70 (m, 1 H) 7.71(d, J = 8.59 Hz, 1 H) 8.17 (dt, J = 7.74, 1.43 Hz, 1 H) 8.35 (br. s., 1H) 63cw ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.44-1.69 (m, 4 H) 1.91 (dd, J= 13.28, 9.18 Hz, 1 H) 2.35 (dd, J = 13.15, 8.61 Hz, 1 H) 3.14 (br. s.,2 H) 3.64 (br. s., 4 H) 4.37-4.53 (m, 1 H) 5.87 (br. s., 1 H) 6.62 (q, J= 6.78 Hz, 1 H) 7.43 (t, J = 1.22 Hz, 1 H) 7.65 (s, 2 H) 7.70 (d, J =4.78 Hz, 2 H) 7.99-8.12 (m, 1 H) 8.26 (br. s., 1 H) 8.96 (d, J = 5.03Hz, 1 H) 10.25 (br. s., 1 H) 63cx ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33(t, J = 7.15 Hz, 3 H) 1.55-1.74 (m, 4 H) 2.04 (dd, J = 13.57, 8.79 Hz, 1H) 2.48 (dd, J = 13.54, 8.76 Hz, 1 H) 3.26 (s, 2 H) 3.44-3.73 (m, 4 H)4.25-4.41 (m, 2 H) 4.56 (t, J = 8.74 Hz, 1 H) 5.57 (s, 1 H) 6.63 (q, J =6.80 Hz, 1 H) 7.30 (d, J = 2.20 Hz, 1 H) 7.47 (dd, J = 8.52, 2.22 Hz, 1H) 7.52-7.59 (m, 1 H) 7.59-7.65 (m, 1 H) 7.67 (d, J = 8.54 Hz, 1 H)7.90-8.04 (m, 1 H) 8.41 (br. s., 1 H) 63cy ¹H NMR (400 MHz, MeOH-d4): δppm 1.33 (t, J = 7.15 Hz, 3 H) 1.53-1.74 (m, 4 H) 2.05 (dd, J = 13.57,8.79 Hz, 1 H) 2.48 (dd, J = 13.54, 8.76 Hz, 1 H) 3.23 (s, 3 H) 3.27 (d,J = 1.22 Hz, 2 H) 3.42-3.79 (m, 4 H) 4.22-4.42 (m, 2 H) 4.57 (t, J =8.79 Hz, 1 H) 5.54 (s, 1 H) 6.61 (q, J = 6.72 Hz, 1 H) 7.35 (d, J = 2.20Hz, 1 H) 7.52 (dd, J = 8.54, 2.25 Hz, 1 H) 7.72 (d, J = 8.54 Hz, 1 H)7.77 (d, J = 7.86 Hz, 2 H) 8.08-8.20 (m, 2 H) 63cz ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.33 (t, J = 7.13 Hz, 3 H) 1.54-1.72 (m, 4 H) 1.99-2.07(m, 1 H) 2.46 (dd, J = 13.57, 8.74 Hz, 1 H) 3.17-3.28 (m, 2 H) 3.42-3.72(m, 4 H) 4.26-4.39 (m, 2 H) 4.51 (t, J = 8.69 Hz, 1 H) 5.53 (s, 1 H)6.56-6.66 (m, 1 H) 7.34 (d, J = 2.20 Hz, 1 H) 7.51 (dd, J = 8.52, 2.22Hz, 1 H) 7.67 (d, J = 8.00 Hz, 2 H) 7.71 (d, J = 8.49 Hz, 1 H) 8.02-8.14(m, 2 H) 63da ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.99 (t, J = 7.15 Hz, 3H) 1.33 (t, J = 7.13 Hz, 3 H) 1.62-1.78 (m, 4 H) 2.07 (dd, J = 13.64,8.86 Hz, 1 H) 2.41 (s, 3 H) 2.50 (dd, J = 13.67, 8.79 Hz, 1 H) 3.29-3.31(m, 2 H) 3.55-3.84 (m, 4 H) 3.84-4.06 (m, 2 H) 4.23-4.42 (m, 2 H) 4.60(t, J = 8.81 Hz, 1 H) 6.23-6.36 (m, 1 H) 6.43 (d, J = 2.34 Hz, 1 H)6.89-7.01 (m, 1 H) 7.40 (dd, J = 7.66, 0.93 Hz, 1 H) 7.48-7.59 (m, 4 H)7.60-7.69 (m, 1 H) 7.86 (dd, J = 7.79, 1.24 Hz, 1 H) 7.93 (d, J = 2.34Hz, 1 H) 63db ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (t, J = 7.15 Hz, 3H) 1.40 (t, J = 7.13 Hz, 3 H) 1.52-1.67 (m, 4 H) 2.00 (dd, J = 13.59,8.81 Hz, 1 H) 2.39 (s, 3 H) 2.44 (dd, J = 13.64, 8.76 Hz, 1 H) 3.17-3.27(m, 2 H) 3.41-3.73 (m, 4 H) 4.23-4.36 (m, 2 H) 4.40 (q, J = 7.13 Hz, 2H) 4.54 (t, J = 8.79 Hz, 1 H) 5.78 (s, 1 H) 6.41 (d, J = 2.15 Hz, 1 H)6.92 (q, J = 6.62 Hz, 1 H) 7.52 (d, J = 8.25 Hz, 1 H) 7.58 (t, J = 7.74Hz, 1 H) 7.77-7.87 (m, 2 H) 7.88-7.97 (m, 2 H) 8.03 (dt, J = 7.79, 1.33Hz, 1 H) 8.21 (t, J = 1.61 Hz, 1 H) 63dc ¹H NMR (400 MHz, MeOH-d4): δppm 1.32 (t, J = 7.13 Hz, 3 H) 1.41 (t, J = 7.13 Hz, 3 H) 1.56-1.69 (m,4 H) 2.03 (dd, J = 13.62, 8.83 Hz, 1 H) 2.41 (s, 3 H) 2.47 (dd, J =13.57, 8.79 Hz, 1 H) 3.26 (s, 2 H) 3.46-3.75 (m, 4 H) 4.32 (qd, J =7.15, 2.37 Hz, 2 H) 4.40 (q, J = 7.14 Hz, 2 H) 4.57 (t, J = 8.79 Hz, 1H) 5.87 (s, 1 H) 6.43 (d, J = 2.34 Hz, 1 H) 6.89-7.03 (m, 1 H) 7.55 (d,J = 8.30 Hz, 1 H) 7.68-7.79 (m, 2 H) 7.87 (dd, J = 8.30, 2.15 Hz, 1 H)7.94 (d, J = 2.34 Hz, 1 H) 7.98 (d, J = 1.51 Hz, 1 H) 8.08-8.18 (m, 2 H)63dd ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.15 Hz, 3 H)1.50-1.71 (m, 4 H) 2.00 (dd, J = 13.54, 8.61 Hz, 1 H) 2.38 (s, 3 H) 2.42(dd, J = 13.59, 8.81 Hz, 1 H) 3.12-3.28 (m, 2 H) 3.42-3.77 (m, 6 H)4.21-4.39 (m, 2 H) 4.48 (t, J = 8.69 Hz, 1 H) 4.69-4.79 (m, 1 H) 5.72(d, J = 2.05 Hz, 1 H) 6.39 (d, J = 2.29 Hz, 1 H) 6.77 (q, J = 6.54 Hz, 1H) 7.45 (d, J = 1.56 Hz, 1 H) 7.52 (dd, J = 8.20, 1.56 Hz, 1H) 7.70 (d,J = 8.15 Hz, 1 H) 7.88 (dd, J = 4.37, 2.37 Hz, 1 H) 63de ¹H NMR (400MHz, MeOH-d4): δ ppm 1.22-1.29 (m, 3 H) 1.51 (dt, J = 11.74, 5.65 Hz, 4H) 1.75 (dd, J = 12.98, 7.32 Hz, 1 H) 1.90 (s, 4 H) 2.09 (dd, J = 13.13,8.74 Hz, 1 H) 2.38 (s, 3 H) 2.73-2.93 (m, 2 H) 3.43-3.63 (m, 4 H) 3.85(dd, J = 8.71, 7.39 Hz, 1 H) 4.10 (s, 2 H) 4.13-4.23 (m, 2 H) 5.70 (s, 1H) 6.41 (d, J = 2.25 Hz, 1 H) 6.78 (q, J = 6.88 Hz, 1 H) 7.52 (d, J =8.35 Hz, 2 H) 7.66 (d, J = 1.71 Hz, 1 H) 7.72-7.84 (m, 4 H) 7.97 (d, J =2.34 Hz, 1 H) 63df ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (dt, J = 10.30,7.13 Hz, 6 H) 1.50-1.69 (m, 4 H) 2.01 (dd, J = 13.57, 8.74 Hz, 1 H)2.40-2.45 (m, 1 H), 2.41 (s, 3 H) 3.22 (d, J = 2.00 Hz, 2 H) 3.44-3.74(m, 4 H) 4.21-4.36 (m, 4 H) 4.52 (t, J = 8.74 Hz, 1 H) 5.80 (s, 1 H)6.43 (d, J = 2.29 Hz, 1 H) 6.61 (d, J = 16.06 Hz, 1 H) 6.92 (q, J = 6.65Hz, 1 H) 7.49-7.56 (m, 2 H) 7.61-7.70 (m, 2 H) 7.72-7.80 (m, 2 H) 7.83(dd, J = 8.27, 2.17 Hz, 1 H) 7.94 (dd, J = 6.39, 1.85 Hz, 2 H) 63dg ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.26-1.39 (m, 6 H) 1.52-1.63 (m, 4 H) 1.94(dd, J = 13.50, 8.32 Hz, 1 H) 2.34 (dd, J = 13.40, 8.76 Hz, 1 H) 2.40(s, 3 H) 3.04-3.20 (m, 2 H) 3.44-3.69 (m, 4 H)4.21-4.31 (m, 4 H) 4.34(t, J = 8.54 Hz, 1 H) 5.78 (s, 1 H) 6.42 (d, J = 2.20 Hz, 1 H) 6.58 (d,J = 16.06 Hz, 1 H) 6.92 (q, J = 6.67 Hz, 1 H) 7.51 (d, J = 8.25 Hz, 1 H)7.62-7.77 (m, 5 H) 7.82 (dd, J = 8.30, 2.15 Hz, 1 H) 7.93 (d, J = 2.34Hz, 1 H) 7.97 (d, J = 1.27 Hz, 1 H) 63dh ¹H NMR (400 MHz, MeOH-d4): δppm 1.18 (t, J = 7.13 Hz, 3 H) 1.32 (t, J = 7.15 Hz, 3 H) 1.54-1.68 (m,4 H) 2.03 (dd, J = 13.62, 8.83 Hz, 1 H) 2.40 (s, 3 H) 2.46 (dd, J =13.59, 8.76 Hz, 1 H) 2.68 (t, J = 7.47 Hz, 2 H) 3.01 (t, J = 7.49 Hz, 2H) 3.25 (s, 2 H) 3.45-3.75 (m, 4 H) 4.10 (q, J = 7.13 Hz, 2 H) 4.25-4.40(m, 2 H) 4.57 (t, J = 8.79 Hz, 1 H) 5.82 (s, 1 H) 6.42 (d, J = 2.25 Hz,1 H) 6.88 (q, J = 6.70 Hz, 1 H) 7.27 (d, J = 7.42 Hz, 1 H) 7.36-7.42 (m,1 H) 7.42-7.47 (m, 2 H) 7.50 (d, J = 8.30 Hz, 1 H) 7.79 (dd, J = 8.27,2.12 Hz, 1 H) 7.88-7.94 (m, 2 H) 63di ¹H NMR (400 MHz, MeOH-d4): δ ppm1.22 (t, J = 7.13 Hz, 3 H) 1.32 (t, J = 7.15 Hz, 3 H) 1.53-1.72 (m, 4 H)2.03 (dd, J = 13.62, 8.83 Hz, 1 H) 2.40 (s, 3 H) 2.47 (dd, J = 13.59,8.76 Hz, 1 H) 2.67 (t, J = 7.57 Hz, 2 H) 2.92-3.03 (m, 2 H) 3.25 (s, 2H) 3.45-3.80 (m, 4 H) 4.11 (q, J = 7.13 Hz, 2 H) 4.32 (qd, J = 7.13,2.32 Hz, 2 H) 4.57 (t, J = 8.79 Hz, 1 H) 5.84 (s, 1 H) 6.41 (d, J = 2.34Hz, 1 H) 6.87 (q, J = 6.57 Hz, 1 H) 7.34 (d, J = 8.25 Hz, 2 H) 7.49 (d,J = 8.30 Hz, 1 H) 7.53 (d, J = 8.25 Hz, 2 H) 7.78 (dd, J = 8.30, 2.15Hz, 1 H) 7.90 (d, J = 2.24 Hz, 2 H) 63dj ¹H NMR (400 MHz, MeOH-d4): δppm 1.20-1.35 (m, 3 H) 1.42-1.60 (m, 4 H) 1.68-1.83 (m, 1 H) 1.99-2.15(m, 1 H) 2.42 (s, 3 H) 2.75 (d, J = 10.93 Hz, 1 H) 2.89 (d, J = 10.93Hz, 1 H) 3.55 (d, J = 5.86 Hz, 4 H) 3.82 (s, 1 H) 4.20 (dd, J = 7.13,1.27 Hz, 2 H) 5.74 (s, 1 H) 6.44 (d, J = 2.15 Hz, 1 H) 6.85 (d, J = 6.64Hz, 1 H) 7.04-7.24 (m, 1 H) 7.39-7.53 (m, 3 H) 7.67 (d, J = 1.56 Hz, 1H) 7.76 (d, J = 1.76 Hz, 1 H) 7.79-7.88 (m, 1 H) 8.01 (d, J = 2.15 Hz, 1H) 63dk ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.13 Hz, 3 H)1.42-1.63 (m, 4 H) 1.69-1.82 (m, 1 H) 2.01-2.16 (m, 1 H) 2.44 (s, 3 H)2.77 (s, 1 H) 2.89 (s, 1 H) 3.57 (d, J = 5.86 Hz, 4 H) 3.76-3.89 (m, 1H) 4.19 (dd, J = 7.22, 1.37 Hz, 2 H) 5.78 (s, 1 H) 6.46 (d, J = 2.15 Hz,1 H) 6.78-6.96 (m, 1 H) 7.53-7.65 (m, 1 H) 7.79-7.98 (m, 3 H) 8.06 (d, J= 2.34 Hz, 1 H) 8.14 (s, 2 H) 8.28 (s, 1 H) 8.40-8.52 (m, 1 H) 8.80-8.96(m, 1 H) 63dl ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.13 Hz, 3H) 1.51-1.68 (m, 4 H) 1.96-2.06 (m, 1 H) 2.39 (s, 3 H) 2.43 (dd, J =13.54, 8.81 Hz, 1 H) 3.15-3.27 (m, 2 H) 3.43-3.72 (m, 4 H) 4.26-4.36 (m,2 H) 4.39-4.45 (m, 1 H) 4.49 (t, J = 8.69 Hz, 1 H) 4.90 (t, J = 8.44 Hz,1 H) 5.70 (d, J = 2.83 Hz, 1 H) 5.87 (td, J = 7.86, 1.66 Hz, 1 H) 6.42(d, J = 2.34 Hz, 1 H) 6.79-6.91 (m, 1 H) 7.52 (t, J = 1.85 Hz, 1 H) 7.58(dt, J = 8.20, 2.17 Hz, 1 H) 7.82 (dd, J = 8.27, 1.54 Hz, 1 H) 7.95 (dd,J = 3.44, 2.61 Hz, 1 H) 63dm ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J= 7.13 Hz, 3 H) 1.43-1.62 (m, 4 H) 1.70-1.83 (m, 1 H) 2.03-2.18 (m, 1 H)2.79 (s, 1 H) 2.90 (s, 1 H) 3.09 (s, 2 H) 3.17 (s, 3 H) 3.54 (br. s., 4H) 3.65 (t, J = 6.74 Hz, 2 H) 3.80-3.96 (m, 1 H) 4.21 (d, J = 7.03 Hz, 2H) 5.57 (s, 1 H) 6.60-6.76 (m, 1 H) 7.52 (s, 1 H) 7.56-7.67 (m, 3 H)7.68-7.79 (m, 2 H) 8.01 (d, J = 8.20 Hz, 1 H) 63dn ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (t, J = 7.13 Hz, 3 H) 1.55 (dt, J = 11.03, 5.37 Hz,4 H) 1.89 (dd, J = 13.32, 8.10 Hz, 1 H) 1.96 (s, 3 H) 1.97 (s, 3 H) 2.28(dd, J = 13.40, 8.86 Hz, 1 H) 2.36 (s, 3 H) 2.97-3.11 (m, 2 H) 3.41-3.68(m, 4 H) 4.18-4.30 (m, 3 H) 4.39 (s, 2 H) 5.69 (s, 1 H) 6.37 (d, J =2.34 Hz, 1 H) 6.73 (q, J = 6.30 Hz, 1 H) 7.31 (d, J = 1.51 Hz, 1 H) 7.40(dd, J = 8.13, 1.59 Hz, 1 H), 7.67 (d, J = 8.05 Hz, 1 H), 7.85 (d, J =2.25 Hz, 1 H) 63do ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (t, J = 7.15Hz, 3 H) 1.55-1.68 (m, 4 H) 1.97 (s, 1 H) 2.02 (dd, J = 13.59, 8.96 Hz,1 H) 2.12 (ddt, J = 13.30, 7.49, 5.74, 5.74 Hz, 1 H) 2.39 (s, 3 H) 2.46(dd, J = 13.57, 8.64 Hz, 1 H) 2.65-2.77 (m, 1 H) 2.91 (dt, J = 13.74,7.04 Hz, 1 H) 3.04-3.14 (m, 1 H) 3.24 (d, J = 1.76 Hz, 2 H) 3.45-3.76(m, 6 H) 3.81 (dd, J = 8.52, 5.88 Hz, 1 H) 4.25-4.45 (m, 4 H) 4.55 (t, J= 8.79 Hz, 1 H) 5.81 (s, 1 H) 6.41 (d, J = 2.29 Hz, 1 H) 6.82 (q, J =6.65 Hz, 1 H) 7.71 (s, 1 H) 7.77-7.84 (m, 4 H) 7.90-8.01 (m, 3 H) 63dp¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 7.13 Hz, 3 H) 1.54-1.75(m, 4 H) 2.02 (dd, J = 13.57, 8.69 Hz, 1 H) 2.28 (s, 3 H) 2.31 (s, 3 H)2.45 (dd, J = 13.54, 8.76 Hz, 1 H) 3.20-3.27 (m, 2 H) 3.23 (s, 3 H)3.42-3.79 (m, 4 H) 4.32 (qd, J = 7.13, 2.54 Hz, 2 H) 4.51 (t, J = 8.69Hz, 1 H) 5.63 (s, 1 H) 6.63 (q, J = 6.64 Hz, 1 H) 7.19 (d, J = 7.86 Hz,1 H) 7.36 (dd, J = 7.76, 1.76 Hz, 1 H) 7.41 (s, 1 H) 7.48 (d, J = 1.81Hz, 1 H) 7.65-7.72 (m, 1 H) 7.72-7.77 (m, 1 H) 7.80-7.85 (m, 2 H) 8.07(dt, J = 7.03, 1.93 Hz, 1 H) 8.47 (br. s., 1 H) 63dq ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.32 (t, J = 7.13 Hz, 3 H) 1.53-1.73 (m, 4 H) 1.93-2.08(m, 1 H) 2.41 (dd, J = 13.45, 8.71 Hz, 1 H) 3.11-3.23 (m, 2 H) 3.24 (s,3 H) 3.46-3.79 (m, 4 H) 4.30 (qd, J = 7.12, 2.46 Hz, 2 H) 4.43 (t, J =8.59 Hz, 1 H) 5.65 (s, 1 H) 6.67 (q, J = 6.64 Hz, 1 H) 7.56 (dd, J =8.32, 4.32 Hz, 1 H) 7.70 (d, J = 1.76 Hz, 1 H) 7.78-7.97 (m, 4 H) 8.07 δ8.12 (m, 3 H) 8.23 (s, 1 H), 8.42 (dd, J = 8.44, 1.61 Hz, 1 H) 8.53 (br.s., 1 H) 8.85 (dd, J = 4.32, 1.68 Hz, 1 H) 63dr ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.32 (t, J = 7.13 Hz, 3 H) 1.51-1.71 (m, 4 H) 1.99-2.08(m, 1 H) 2.40 (s, 3 H) 2.41 (s, 3 H) 2.46 (dd, J = 13.62, 8.74 Hz, 1 H)3.25 (d, J = 1.07 Hz, 2 H) 3.43-3.77 (m, 4 H) 4.32 (qd, J = 7.13, 2.32Hz, 2 H) 4.57 (t, J = 8.79 Hz, 1 H) 4.68 (s, 2 H) 5.85 (s, 1 H) 6.42 (d,J = 2.25 Hz, 1 H) 6.88 (q, J = 6.65 Hz, 1 H) 7.34-7.54 (m, 4 H) 7.79(dd, J = 8.27, 2.12 Hz, 1 H) 7.91 (d, J = 2.25 Hz, 2 H) 63ds ¹H NMR (400MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.15 Hz, 3 H) 1.55-1.77 (m, 4 H) 2.04(dd, J = 9.32, 4.30 Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H) 2.48 (dd, J =13.62, 8.79 Hz, 1 H) 3.28 (s, 2 H) 3.50-3.87 (m, 4 H) 4.19-4.42 (m, 2 H)4.59 (t, J = 8.79 Hz, 1 H) 4.71 (s, 2 H) 6.14 (br. s., 1 H) 6.42 (d, J =2.34 Hz, 1 H) 6.91 (q, J = 6.41 Hz, 1 H) 7.28 (d, J = 7.91 Hz, 1 H) 7.44(dd, J = 7.76, 2.05 Hz, 1 H) 7.51 (d, J = 8.25 Hz, 1 H) 7.65 (d, J =1.81 Hz, 1 H) 7.85 (dd, J = 8.27, 2.12 Hz, 1 H) 7.88-7.96 (m, 2 H) 63dt¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.13 Hz, 3 H) 1.52-1.71(m, 4 H) 1.98-2.08 (m, 1 H) 2.41 (s, 3 H) 2.45 (dd, J = 13.62, 8.79 Hz,1 H) 3.24 (d, J = 1.61 Hz, 2 H) 3.42-3.73 (m, 4 H) 3.93 (s, 3 H)4.24-4.40 (m, 2 H) 4.54 (t, J = 8.76 Hz, 1 H) 5.78 (s, 1 H) 6.43 (d, J =2.29 Hz, 1 H) 6.95 (q, J = 6.62 Hz, 1 H) 7.54 (d, J = 8.30 Hz, 1 H)7.67-7.77 (m, 2 H) 7.85 (dd, J = 8.30, 2.20 Hz, 1 H) 7.94 (d, J = 2.34Hz, 1 H) 7.98 (d, J = 1.37 Hz, 1 H) 8.07-8.16 (m, 2 H) 63du ¹H NMR (400MHz, MeOH-d4): δ ppm 1.29 (t, J = 7.13 Hz, 3 H) 1.46-1.67 (m, 4 H) 1.90(dd, J = 13.35, 8.22 Hz, 1 H) 2.30 (dd, J = 13.35, 8.71 Hz, 1 H) 2.40(s, 3 H) 2.93-3.16 (m, 2 H) 3.38-3.74 (m, 4 H) 4.16-4.36 (m, 3 H) 5.77(s, 1 H) 6.41 (d, J = 2.29 Hz, 1 H) 6.91 (q, J = 6.62 Hz, 1 H) 7.51 (d,J = 8.25 Hz, 1 H) 7.64 (d, J = 8.40 Hz, 2 H) 7.82 (dd, J = 8.30, 2.15Hz, 1 H) 7.93 (d, J = 2.29 Hz, 1 H) 7.96 (s, 1 H) 8.07 (d, J = 8.30 Hz,2 H) 63dv ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (s, 4 H) 1.60-1.76 (m, 3H) 2.02-2.13 (m, 1 H) 2.43 (s, 3 H) 2.46-2.56 (m, 1 H) 3.30 (s, 2 H)3.53-3.83 (m, 4 H) 4.30-4.40 (m, 2 H) 4.56-4.66 (m, 1 H) 5.48 (s, 2 H)6.01-6.11 (m, 1 H) 6.44-6.50 (m, 1 H) 6.89-6.98 (m, 1 H) 7.80-7.84 (m, 1H) 7.86-8.02 (m, 5 H) 8.03-8.08 (m, 1 H) 63dw ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.28 (t, J = 7.13 Hz, 3 H) 1.55 (br. s., 4 H) 1.70-1.83 (m, 1 H)2.03-2.18 (m, 1 H) 2.70-2.82 (m, 1 H) 2.86-2.97 (m, 1 H) 3.41-3.59 (m, 4H) 3.79-3.94 (m, 1 H) 4.09-4.30 (m, 2 H) 5.59 (s, 1 H) 6.60-6.77 (m, 1H) 7.71 (d, J = 8.20 Hz, 2 H) 7.84 (d, J = 8.20 Hz, 2 H) 8.03-8.15 (m, 1H) 8.34 (s, 2 H) 9.26 (s, 1 H) 9.59 (s, 1 H) 63dx ¹H NMR (400 MHz,Chloroform-d): δ ppm 1.27 (m, 7H), 1.55 (m, 3H), 1.77 (dd, J = 13.1, 7.0Hz, 1H), 2.11 (dd, J = 13.1, 8.9 Hz, 1H), 2.42 (s, 3H), 2.96 (m, 2H),3.47 (dt, J = 11.6, 5.7 Hz, 4H), 3.98 (dd, J = 8.8, 6.9 Hz, 1H), 4.21(q, J = 7.1 Hz, 2H), 4.73 (s, 2H), 5.49 (s, 1H), 5.99 (m, 1H), 6.35 (d,J = 2.3 Hz, 1H), 6.63 (q, J = 6.7 Hz, 1H), 7.61 (m, 2H), 7.73 (d, J =2.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 8.96 (s, 2H), 9.24 (s, 1H) 63dy¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 8H), 1.51 (dt, J = 10.8, 5.6Hz, 8H), 1.74 (dd, J = 13.1, 7.3 Hz, 2H), 2.06 (m, 2H), 2.39 (s, 6H),2.75 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 2H), 3.53 (dt, J =22.5, 6.4 Hz, 8H), 3.82 (dd, J = 8.8, 7.2 Hz, 2H), 4.18 (qd, J = 7.1,1.6 Hz, 3H), 5.73 (s, 2H), 6.00 (m, 1H), 6.42 (d, J = 2.4 Hz, 2H), 6.82(q, J = 6.6 Hz, 2H), 7.35 (dt, J = 10.4, 8.4 Hz, 2H), 7.50 (m, 2H), 7.73(m, 8H), 8.00 (d, J = 2.4 Hz, 2H) 63dz ¹H NMR (400 MHz, MeOH-d4): δ ppm1.26 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J =13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74(d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 23.8,7.6, 6.5 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6Hz, 2H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.80 (q, J = 6.5 Hz,1H), 7.46 (m, 2H), 7.71 (m, 5H), 7.98 (d, J = 2.3 Hz, 1H) 63ea ¹H NMR(400 MHz, DMSO-d6): δ ppm 1.25 (t, J = 7.10 Hz, 3 H) 1.42-1.69 (m, 4 H)1.92 (dd, J = 13.25, 9.35 Hz, 1 H) 2.35 (dd, J = 13.25, 8.47 Hz, 1 H)3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J = 7.09, 2.10 Hz, 2 H)4.54 (br. s., 1 H) 5.77 (br. s., 1 H) 6.70 (q, J = 6.65 Hz, 1 H) 7.37(d, J = 2.10 Hz, 1 H) 7.43-7.52 (m, 3 H) 7.53-7.69 (m, 4 H) 9.23 (br.s., 1 H) 10.44 (br. s., 1 H) 63eb ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25(t, J = 7.1 Hz, 4H), 1.49 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J =13.1, 7.2 Hz, 1H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74(d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.82 (dd,J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.76 (s, 1H), 6.41(d, J = 2.4 Hz, 1H), 6.89 (q, J = 6.6 Hz, 1H), 7.51 (m, 6H), 7.76 (dd, J= 8.3, 2.2 Hz, 1H), 7.92 (t, J = 2.2 Hz, 2H) 63ec ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.51 (dt, J = 10.1, 5.3 Hz,4H), 1.77 (dd, J = 13.1, 7.4 Hz, 1H), 2.12 (dd, J = 13.2, 8.8 Hz, 1H),2.39 (s, 3H), 2.80 (d, J = 11.1 Hz, 1H), 2.93 (d, J = 11.1 Hz, 1H), 3.53(m, 4H), 3.91 (t, J = 8.0 Hz, 1H), 4.19 (qd, J = 7.2, 1.7 Hz, 2H), 5.77(s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.91 (q, J = 6.6 Hz, 1H), 7.37 (ddt,J = 16.6, 10.3, 8.6 Hz, 2H), 7.51 (m, 2H), 7.76 (dd, J = 8.3, 2.2 Hz,1H), 7.91 (dd, J = 9.9, 2.4 Hz, 2H) 63ed ¹H NMR (400 MHz, MeOH-d4): δppm 1.26 (m, 6H), 1.50 (dt, J = 10.4, 5.4 Hz, 5H), 1.73 (dd, J = 13.1,7.2 Hz, 1H), 2.06 (m, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88(d, J = 11.0 Hz, 1H), 3.53 (m, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17(qd, J = 7.1, 1.5 Hz, 2H), 5.77 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.87(q, J = 6.7 Hz, 1H), 7.44 (m, 4H), 7.60 (m, 3H), 7.78 (dd, J = 8.3, 2.1Hz, 1H), 7.92 (t, J = 2.6 Hz, 2H) 63ee ¹H NMR (400 MHz, MeOH-d4): δ ppm1.27 (q, J = 8.3, 7.1 Hz, 6H), 1.49 (m, 4H), 1.72 (dd, J = 13.1, 7.2 Hz,1H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.83 (dd, J = 8.8, 7.2Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.77 (s, 1H), 6.41 (d, J = 2.5Hz, 1H), 6.93 (q, J = 6.6 Hz, 1H), 7.50 (m, 2H), 7.59 (d, J = 8.3 Hz,1H), 7.73 (m, 2H), 7.92 (dd, J = 7.7, 2.3 Hz, 2H) 63ef ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 5H), 1.54 (tt, J = 7.3, 4.4 Hz,4H), 1.80 (dd, J = 13.2, 7.6 Hz, 1H), 2.17 (dd, J = 13.2, 8.8 Hz, 1H),2.85 (d, J = 11.2 Hz, 1H), 2.97 (d, J = 11.2 Hz, 1H), 3.52 (ddt, J =28.3, 12.4, 8.0 Hz, 4H), 3.97 (dd, J = 8.8, 7.5 Hz, 1H), 4.21 (qd, J =7.1, 1.7 Hz, 2H), 5.50 (s, 1H), 6.68 (q, J = 6.9 Hz, 1H), 7.25 (m, 4H),7.48 (m, 3H), 7.71 (m, 1H) 63eg ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26(t, J = 7.3 Hz, 4H), 1.51 (dt, J = 11.2, 5.5 Hz, 4H), 1.75 (dd, J =13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.78(d, J = 11.1 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.53 (m, 5H), 3.86 (dd,J = 8.6, 7.4 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.77 (s, 1H), 6.44(d, J = 2.4 Hz, 1H), 7.00 (q, J = 6.7 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H),7.97 (m, 3H), 9.06 (s, 2H), 9.17 (s, 1H) 63eh ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.52 (dq, J = 12.0, 8.6, 7.2 Hz, 4H),1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.75(d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.51 (m, 4H), 3.82 (dd,J = 8.7, 7.1 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.52 (s, 1H), 6.61(q, J = 6.7 Hz, 1H), 7.33 (m, 2H), 7.47 (m, 2H), 7.66 (m, 2H) 63ei ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.1, 1.7 Hz, 6H), 1.41 (td,J = 7.0, 1.8 Hz, 3H), 1.52 (qd, J = 7.2, 4.7, 3.6 Hz, 4H), 1.75 (dd, J =13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 10.9Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.29 (s, 1H), 3.51 (dq, J = 18.9,6.1 Hz, 4H), 3.84 (m, 1H), 4.16 (m, 3H), 5.48 (d, J = 2.0 Hz, 1H), 6.73(q, J = 6.8 Hz, 1H), 7.02 (m, 2H), 7.20 (s, 1H), 7.28 (d, J = 2.2 Hz,1H), 7.43 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H) 63ej ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (m, 4H), 1.50 (dt, J = 22.1, 6.5 Hz, 7H), 1.74 (dd,J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J =11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.31 (d, J = 1.8 Hz, 1H), 3.49(dq, J = 25.8, 7.5, 6.6 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18(m, 4H), 5.49 (s, 1H), 6.62 (q, J = 6.8 Hz, 1H), 7.20 (d, J = 8.5 Hz,1H), 7.26 (d, J = 2.2 Hz, 1H), 7.34 (m, 1H), 7.42 (dd, J = 8.5, 2.2 Hz,1H), 7.58 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H) 63ek ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (t, J = 7.0 Hz, 4H), 1.53 (m, 4H), 1.75 (dd, J =13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 10.9Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.51 (dq, J = 26.1, 7.5, 6.6 Hz,4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H),5.53 (s, 1H), 6.59 (q, J = 6.7 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.34(m, 2H), 7.49 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H) 63el ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.89 (m, 2H), 1.31 (m, 15H), 1.52 (dt, J = 7.9, 4.5 Hz,4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H),2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.49 (ddt, J =17.6, 11.8, 6.7 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J =7.2, 1.5 Hz, 2H), 5.44 (s, 1H), 6.60 (q, J = 6.8 Hz, 1H), 7.28 (m, 2H),7.47 (m, 4H), 7.67 (d, J = 8.5 Hz, 1H) 63em ¹H NMR (400 MHz, MeOH-d4): δppm 1.26 (m, 6H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10(dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 10.9 Hz, 1H), 2.91 (d, J = 11.0Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J =7.1, 1.7 Hz, 2H), 5.53 (s, 1H), 6.47 (q, J = 6.7 Hz, 1H), 7.36 (d, J =2.2 Hz, 1H), 7.53 (dd, J = 8.6, 2.3 Hz, 1H), 7.72 (m, 2H), 7.85 (m, 2H)63en ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (t, J = 7.1 Hz, 7H), 1.59(dt, J = 11.5, 5.7 Hz, 8H), 1.95 (m, 2H), 2.34 (dd, J = 13.3, 8.6 Hz,2H), 3.10 (m, 4H), 3.56 (m, 8H), 3.75 (s, 1H), 4.28 (m, 6H), 5.55 (s,1H), 6.52 (q, J = 6.7 Hz, 2H), 7.38 (d, J = 2.2 Hz, 2H), 7.53 (dd, J =8.5, 2.2 Hz, 2H), 7.66 (m, 8H) 63eo ¹H NMR (400 MHz, MeOH-d4): δ ppm1.26 (td, J = 7.0, 0.7 Hz, 4H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.3Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H),2.90 (d, J = 11.0 Hz, 1H), 3.30 (m, 1H), 3.51 (dtd, J = 19.2, 13.4, 7.5Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (m, 2H), 5.50 (s, 1H),6.63 (q, J = 6.9 Hz, 1H), 7.25 (m, 1H), 7.47 (m, 6H), 7.71 (m, 1H) 63ep¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 7.1 Hz, 4H), 1.65 (m, 5H),2.06 (dd, J = 13.6, 8.9 Hz, 1H), 2.50 (dd, J = 13.6, 8.8 Hz, 1H), 3.28(s, 2H), 3.57 (m, 5H), 3.86 (s, 3H), 4.32 (qd, J = 7.2, 2.5 Hz, 2H),4.59 (t, J = 8.8 Hz, 1H), 6.68 (q, J = 6.7 Hz, 1H), 6.98 (d, J = 7.5 Hz,1H), 7.07 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.46 (m, 2H), 7.68 (d, J =8.5 Hz, 1H) 63eq ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 10H), 1.52(m, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz,1H), 2.75 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H),3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 4.70 (h,J = 6.1 Hz, 1H), 5.48 (s, 1H), 6.73 (q, J = 6.9 Hz, 1H), 6.95 (d, J =7.6 Hz, 1H), 7.04 (m, 1H), 7.21 (s, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.42(m, 2H), 7.66 (d, J = 8.5 Hz, 1H) 63er ¹H NMR (400 MHz, MeOH-d4): δ ppm1.26 (td, J = 7.1, 1.4 Hz, 3H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.2Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.46 (s, 3H), 2.76 (d, J =10.9 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J =8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.50 (d, J = 1.5 Hz,1H), 6.60 (q, J = 6.8 Hz, 1H), 7.29 (m, 2H), 7.45 (m, 2H), 7.57 (s, 1H),7.67 (m, 1H) 63es ¹H NMR (400 MHz, MeOH-d4): δ ppm: 1.19 (s, 2H), 1.34(m, 11H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J =13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H),3.52 (m, 4H), 3.83 (m, 1H), 4.18 (m, 2H), 4.73 (h, J = 6.1 Hz, 1H), 5.50(s, 1H), 6.62 (q, J = 6.6 Hz, 1H), 7.28 (m, 3H), 7.43 (dd, J = 8.5, 2.3Hz, 1H), 7.59 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H) 63et ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.88 (d, J = 8.3 Hz, 1H), 1.30 (m, 11H), 1.53 (m, 4H),1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76(d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (m, 5H), 3.83 (dd,J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.71 (h, J = 6.2Hz, 1H), 5.49 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.27 (m, 4H), 7.43 (dd,J = 8.5, 2.3 Hz, 1H), 7.65 (m, 1H) 63eu ¹H NMR (400 MHz, MeOH-d4): δ ppm1.30 (m, 4H), 1.60 (tt, J = 9.2, 4.2 Hz, 4H), 1.97 (m, 1H), 2.37 (dd, J= 13.6, 8.8 Hz, 1H), 3.14 (q, J = 11.6 Hz, 2H), 3.56 (m, 4H), 4.31 (m,3H), 4.87 (d, J = 1.7 Hz, 18H), 5.54 (s, 1H), 6.49 (q, J = 6.6 Hz, 1H),7.35 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d, J =8.6 Hz, 1H), 7.82 (m, 3H) 63ev ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m,4H), 1.54 (m, 4H), 1.78 (dd, J = 13.1, 7.4 Hz, 1H), 2.13 (dd, J = 13.1,8.8 Hz, 1H), 2.81 (d, J = 11.1 Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 3.53(dq, J = 13.2, 6.0 Hz, 4H), 3.89 (dd, J = 8.8, 7.3 Hz, 1H), 4.20 (qd, J= 7.1, 1.7 Hz, 2H), 5.51 (s, 1H), 6.63 (q, J = 6.7 Hz, 1H), 7.28 (m,4H), 7.52 (m, 2H), 7.68 (d, J = 8.5 Hz, 1H) 63ew ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.90 (d, J = 8.0 Hz, 1H), 1.27 (m, 5H), 1.53 (dt, J =7.7, 4.7 Hz, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1,8.8 Hz, 1H), 2.45 (s, 3H), 2.78 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0Hz, 1H), 3.31 (s, 3H), 3.50 (dq, J = 27.7, 7.7, 6.6 Hz, 4H), 3.85 (t, J= 8.0 Hz, 1H), 4.19 (m, 2H), 5.49 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H),7.32 (m, 3H), 7.45 (dd, J = 8.6, 2.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H),7.67 (d, J = 8.5 Hz, 1H) 63ex ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t,J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11(dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0Hz, 1H), 3.54 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J =7.1, 1.7 Hz, 2H), 5.53 (s, 1H), 6.54 (q, J = 6.7 Hz, 1H), 7.36 (d, J =2.2 Hz, 1H), 7.53 (dd, J = 8.6, 2.2 Hz, 1H), 7.68 (dd, J = 23.2, 8.4 Hz,2H), 7.84 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H) 63ey ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (ddd, J = 11.9, 6.5, 4.3Hz, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz,1H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (dq, J =26.9, 7.7, 6.7 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J =7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 6.63 (q, J = 6.7 Hz, 1H), 7.10 (tt, J =9.2, 2.4 Hz, 1H), 7.19 (s, 2H), 7.34 (d, J = 2.2 Hz, 1H), 7.50 (dd, J =8.6, 2.2 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H) 63ez ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.07 (d, J = 1.0 Hz, 1H), 0.88 (dd, J = 14.3, 7.9 Hz,1H), 1.28 (m, 6H), 1.56 (m, 3H), 1.75 (dd, J = 13.1, 6.7 Hz, 1H), 2.07(dd, J = 13.1, 8.8 Hz, 2H), 2.84 (d, J = 10.5 Hz, 1H), 2.96 (d, J = 10.5Hz, 1H), 3.49 (m, 4H), 3.88 (m, 1H), 4.20 (m, 2H), 4.56 (s, 2H), 5.44(d, J = 1.0 Hz, 1H), 6.52 (q, J = 6.7 Hz, 1H), 7.23 (m, 3H), 7.40 (m,1H), 7.66 (m, 2H) 63fa ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1Hz, 3H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J =13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 10.9 Hz, 1H),3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.6 Hz,2H), 5.52 (s, 1H), 6.60 (q, J = 6.8 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H),7.45 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H) 63fb ¹H NMR (400 MHz, MeOH-d₄): δppm 0.89 (dd, J = 10.8, 3.8 Hz, 1H), 1.27 (t, J = 7.1 Hz, 4H), 1.53 (m,4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H),2.25 (s, 1H), 2.35 (d, J = 3.2 Hz, 6H), 2.77 (d, J = 11.0 Hz, 1H), 2.91(d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.19(qd, J = 7.2, 1.6 Hz, 2H), 4.87 (d, J = 5.2 Hz, 13H), 5.44 (s, 1H), 6.64(q, J = 6.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 7.26 (m, 2H), 7.41 (dd, J= 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H) 63fc ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.89 (t, J = 6.7 Hz, 1H), 1.30 (m, 11H), 1.59 (dt, J =7.7, 4.0 Hz, 9H), 1.94 (dd, J = 13.4, 8.3 Hz, 2H), 2.45 (s, 15H), 2.80(s, 3H), 3.12 (m, 4H), 3.55 (tdd, J = 24.1, 17.0, 12.0 Hz, 9H), 4.28 (m,6H), 5.51 (s, 2H), 6.64 (q, J = 6.8 Hz, 2H), 7.21 (s, 4H), 7.28 (d, J =2.3 Hz, 2H), 7.44 (dd, J = 8.5, 2.3 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H)63fd ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.08 (dd, J = 4.2, 1.7 Hz, 1H),0.90 (q, J = 7.7 Hz, 1H), 1.26 (t, J = 7.1 Hz, 4H), 1.50 (dt, J = 33.9,6.4 Hz, 7H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.50 (dq,J = 24.8, 7.5, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (ttd, J= 7.1, 4.5, 2.1 Hz, 4H), 5.49 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.27(m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H) 63fe¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.2, 1.1 Hz, 4H), 1.52(dt, J = 11.8, 5.7 Hz, 4H), 1.74 (dd, J = 13.2, 7.2 Hz, 1H), 2.09 (dd, J= 13.2, 8.7 Hz, 1H), 2.38 (s, 6H), 2.75 (d, J = 11.0 Hz, 1H), 2.90 (d, J= 11.0 Hz, 1H), 3.50 (m, 5H), 3.82 (t, J = 8.0 Hz, 1H), 4.18 (m, 2H),5.45 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.04 (s, 2H), 7.12 (d, J = 1.8Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.41 (m, 1H), 7.66 (d, J = 8.5 Hz,1H) 63ff ¹H NMR (400 MHz, MeOH-d4): δ ppm1.27 (t, J = 7.1 Hz, 3H), 1.54(m, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz,1H), 2.43 (s, 3H), 2.78 (d, J = 11.0 Hz, 1H), 2.92 (d, J = 11.0 Hz, 1H),3.52 (m, 4H), 3.86 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz,2H), 5.50 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H), 7.18 (s, 1H), 7.31 (m, 2H),7.39 (s, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.68 (m, 1H) 63fg ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.9 Hz, 1H), 1.27 (m, 6H), 1.53(dt, J = 7.9, 4.6 Hz, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (m,1H), 2.35 (d, J = 1.9 Hz, 3H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J =11.0 Hz, 1H), 3.49 (dp, J = 25.1, 5.9 Hz, 4H), 3.84 (dd, J = 8.7, 7.2Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.87 (s, 13H), 5.49 (s, 1H),6.62 (q, J = 6.8 Hz, 1H), 7.26 (m, 4H), 7.43 (dd, J = 8.6, 2.3 Hz, 1H),7.66 (d, J = 8.5 Hz, 1H) 63fh ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t,J = 7.1 Hz, 4H), 1.53 (dp, J = 7.3, 3.6, 2.9 Hz, 4H), 1.75 (dd, J =13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.40 (s, 3H), 2.77(d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.51 (m, 4H), 3.84 (dd,J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.50 (s, 1H), 6.61(q, J = 6.7 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.45 (m, 4H), 7.67 (d, J= 8.5 Hz, 1H) 63fi ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz,5H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1,8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.51(dtt, J = 18.9, 13.4, 7.4 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18(qd, J = 7.2, 1.6 Hz, 2H), 5.50 (d, J = 10.3 Hz, 1H), 6.58 (q, J = 6.7Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.47 (m, 4H), 7.67 (m, 2H) 63fj ¹HNMR (400 MHz, MeOH-d4): δ ppm 0.87 (dd, J = 11.5, 4.7 Hz, 1H), 1.26(ddd, J = 19.3, 6.9, 5.5 Hz, 12H), 1.48 (m, 4H), 1.72 (dd, J = 13.1, 7.3Hz, 1H), 2.05 (m, 1H), 2.74 (d, J = 11.0 Hz, 1H), 2.93 (m, 2H), 3.45 (m,4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.4 Hz, 2H),5.44 (s, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.34 (m, 7H), 7.66 (d, J = 8.5Hz, 1H) 63fk ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.9 Hz, 1H),1.19 (s, 2H), 1.26 (t, J = 7.1 Hz, 4H), 1.53 (dt, J = 8.3, 4.9 Hz, 4H),1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76(d, J = 11.0 Hz, 1H), 2.90 (d, J = 10.9 Hz, 1H), 3.51 (m, 4H), 3.83 (dd,J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 4.87 (s, 7H), 5.52(s, 1H), 6.40 (q, J = 6.6 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.55 (dd, J= 8.5, 2.3 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 8.11 (s, 2H) 63fl ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.27 (m, 6H), 1.54 (m, 7H), 1.77 (dd, J =13.1, 7.3 Hz, 2H), 2.12 (dd, J = 13.1, 8.7 Hz, 2H), 2.23 (dd, J = 4.4,1.5 Hz, 3H), 2.36 (d, J = 2.1 Hz, 5H), 2.79 (d, J = 11.1 Hz, 2H), 2.93(d, J = 11.0 Hz, 2H), 3.30 (d, J = 9.7 Hz, 1H), 3.52 (dq, J = 19.4, 6.4Hz, 7H), 3.88 (dd, J = 8.8, 7.3 Hz, 2H), 4.19 (dddd, J = 8.7, 7.1, 5.6,1.7 Hz, 3H), 5.49 (q, J = 2.5, 1.9 Hz, 2H), 6.65 (q, J = 6.7 Hz, 2H),7.22 (m, 6H), 7.43 (m, 3H), 7.67 (d, J = 8.5 Hz, 2H) 63fm ¹H NMR (400MHz, MeOH-d4): δ ppm1.30 (m, 5H), 1.61 (m, 4H), 1.96 (dd, J = 13.4, 8.4Hz, 1H), 2.37 (dd, J = 13.4, 8.7 Hz, 1H), 2.81 (s, 1H), 3.13 (q, J =11.6 Hz, 2H), 3.57 (m, 4H), 4.30 (m, 3H), 5.56 (s, 1H), 6.55 (q, J = 6.7Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.55 (m, 5H), 7.69 (d, J = 8.5 Hz,1H) 63fn ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.53 (m, 4H),1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76(d, J = 10.9 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.51 (m, 4H), 3.82 (dd,J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.53 (s, 1H), 6.49(q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.52 (m, 2H), 7.68 (d, J= 8.6 Hz, 1H), 7.81 (s, 2H) 63fo ¹H NMR (400 MHz, MeOH-d4): δ ppm1.27(t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10(dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.83 (s, 1H),2.91 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H),4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 6.53 (q, J = 6.8 Hz, 1H),7.37 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 (ddd, J =7.9, 5.0, 0.9 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.98 (m, 1H), 8.67 (dd,J = 5.0, 1.6 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H) 63fp ¹H NMR (400 MHz,MeOH-d4): δ ppm1.31 (m, 10H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz,1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.91(d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19(qd, J = 7.1, 1.6 Hz, 2H), 4.69 (p, J = 6.1 Hz, 1H), 5.51 (s, 1H), 6.72(q, J = 7.0 Hz, 1H), 6.83 (dt, J = 11.3, 2.3 Hz, 1H), 7.03 (m, 1H), 7.30(d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.67 (d, J = 8.5Hz, 1H) 63fq ¹H NMR (400 MHz, MeOH-d4): δ ppm0.88 (m, 1H), 1.37 (m,22H), 1.75 (dd, J = 13.1, 7.4 Hz, 2H), 2.09 (dd, J = 13.1, 8.8 Hz, 2H),2.21 (s, 2H), 2.78 (d, J = 11.1 Hz, 2H), 2.91 (d, J = 11.1 Hz, 2H), 3.49(m, 8H), 3.88 (dd, J = 8.8, 7.4 Hz, 2H), 4.12 (m, 8H), 5.49 (s, 2H),6.79 (m, 7H), 7.03 (s, 2H), 7.28 (d, J = 2.3 Hz, 2H), 7.42 (dd, J = 8.6,2.2 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H) 63fr ¹H NMR (400 MHz, MeOH-d4): δppm1.32 (m, 15H), 1.52 (m, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.09(dd, J = 13.1, 8.8 Hz, 1H), 2.32 (d, J = 0.7 Hz, 1H), 2.43 (d, J = 0.8Hz, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.48 (m,4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.5 Hz, 2H),5.43 (s, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.06 (s, 1H), 7.26 (m, 2H), 7.34(q, J = 1.3 Hz, 1H), 7.42 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5Hz, 1H) 63fs ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.2 Hz, 3H),1.55 (m, 4H), 1.77 (dd, J = 13.1, 7.3 Hz, 1H), 2.12 (dd, J = 13.2, 8.8Hz, 1H), 2.79 (d, J = 11.0 Hz, 1H), 2.92 (d, J = 11.0 Hz, 1H), 3.53 (m,4H), 3.86 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H),4.86 (s, 3H), 5.53 (s, 1H), 6.57 (q, J = 6.8 Hz, 1H), 7.34 (d, J = 2.2Hz, 1H), 7.51 (dd, J = 8.5, 2.3 Hz, 1H), 7.72 (m, 2H), 7.84 (m, 2H),7.92 (s, 1H) 63ft ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 2H), 1.24(m, 4H), 1.39 (t, J = 7.0 Hz, 3H), 1.50 (q, J = 7.7, 5.2 Hz, 4H), 1.74(ddd, J = 13.3, 7.3, 1.8 Hz, 1H), 2.08 (ddd, J = 11.4, 8.7, 2.6 Hz, 1H),2.39 (s, 3H), 2.76 (d, J = 11.1 Hz, 1H), 2.88 (dd, J = 11.0, 5.7 Hz,1H), 3.58 (m, 4H), 3.85 (m, 1H), 4.13 (m, 4H), 5.73 (s, 1H), 6.42 (d, J= 2.4 Hz, 1H), 6.70 (dt, J = 10.7, 2.2 Hz, 1H), 6.80 (p, J = 6.5 Hz,1H), 7.01 (m, 2H), 7.63 (d, J = 1.9 Hz, 1H), 7.76 (m, 2H), 8.00 (d, J =2.4 Hz, 1H) 63fu ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz,4H), 1.50 (dt, J = 9.9, 5.2 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H),2.07 (dd, J = 13.1, 8.7 Hz, 1H), 2.22 (s, 1H), 2.29 (d, J = 10.3 Hz,6H), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H),3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz,2H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.75 (m, 1H), 7.19 (d, J =7.9 Hz, 1H), 7.39 (m, 2H), 7.59 (d, J = 1.8 Hz, 1H), 7.72 (m, 2H), 7.96(d, J = 2.3 Hz, 1H) 63fv ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H),1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08(dd, J = 13.1, 8.7 Hz, 1H), 2.39 (s, 1H), 2.76 (d, J = 11.0 Hz, 1H),2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.83 (m, 1H), 4.18 (m, 2H),4.85 (d, J = 10.8 Hz, 1H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.83(q, J = 6.6 Hz, 1H), 7.60 (m, 4H), 7.79 (m, 2H), 8.00 (d, J = 2.4 Hz,1H) 63fw ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.46(m, 7H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (dd, J = 13.1, 8.8 Hz,1H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H),3.52 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, 1H), 4.16 (m, 4H), 5.73 (s,1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.11 (d, J =8.6 Hz, 1H), 7.57 (m, 2H), 7.71 (m, 3H), 7.98 (d, J = 2.4 Hz, 1H) 63fx¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.39 (t, J = 7.0 Hz, 3H),1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.1 Hz, 1H), 2.07(dd, J = 13.0, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, 1H),2.88 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H),4.13 (m, 4H), 4.87 (s, 13H), 5.74 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H),6.78 (q, J = 7.6, 7.0 Hz, 1H), 6.93 (m, 1H), 7.20 (m, 2H), 7.34 (t, J =7.9 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.75 (m, 2H), 7.98 (d, J = 2.4Hz, 1H) 63fy ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 3H), 1.50 (dt, J= 10.5, 5.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J =13.0, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J =11.0 Hz, 1H), 3.52 (m, 4H), 3.80 (m, 1H), 4.17 (qd, J = 7.1, 1.6 Hz,2H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.84 (q, J = 6.6 Hz, 1H),6.99 (tt, J = 9.1, 2.4 Hz, 1H), 7.34 (m, 2H), 7.68 (d, J = 1.9 Hz, 1H),7.79 (m, 2H), 8.01 (d, J = 2.4 Hz, 1H) 63fz ¹H NMR (400 MHz, MeOH-d4): δppm 1.26 (m, 3H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13.1,7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.74 (d, J =11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 25.8, 8.1, 6.9Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H),5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.69(m, 3H), 7.82 (m, 2H), 7.98 (m, 3H) 63ga ¹H NMR (400 MHz, MeOH-d4): δppm 1.27 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.53 (m, 4H),1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (m, 1H), 2.77 (d, J = 11.0 Hz,1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz,1H), 4.17 (m, 4H), 5.49 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.02 (s, 1H),7.27 (m, 3H), 7.45 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H)63gb ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 2H), 1.17 (t, J = 7.0 Hz,1H), 1.31 (m, 12H), 1.51 (dt, J = 11.3, 5.6 Hz, 4H), 1.74 (ddd, J =13.1, 7.3, 1.9 Hz, 1H), 2.08 (ddd, J = 11.9, 8.8, 2.8 Hz, 1H), 2.39 (s,3H), 2.76 (d, J = 11.0 Hz, 1H), 2.89 (dd, J = 11.0, 5.9 Hz, 1H), 3.57(m, 5H), 3.84 (dt, J = 8.6, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 1H),4.64 (p, J = 6.1 Hz, 1H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78(q, J = 6.5 Hz, 1H), 7.16 (t, J = 8.6 Hz, 1H), 7.44 (m, 2H), 7.61 (d, J= 1.9 Hz, 1H), 7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H) 63gc ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 10.6, 5.7 Hz, 4H), 1.74(dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.28 (s,1H), 2.37 (d, J = 16.9 Hz, 9H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J =11.0 Hz, 1H), 3.53 (dt, J = 22.1, 6.0 Hz, 4H), 3.82 (dd, J = 8.7, 7.2Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, 1H), 6.41 (d, J = 2.3Hz, 1H), 6.77 (q, J = 6.6 Hz, 1H), 7.03 (m, 1H), 7.27 (d, J = 1.5 Hz,2H), 7.60 (d, J = 1.8 Hz, 1H), 7.74 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H)63gd ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (q, J = 7.1, 6.4 Hz, 4H),1.50 (dt, J = 10.3, 5.6 Hz, 4H), 1.73 (dd, J = 13.0, 7.2 Hz, 1H), 2.07(dd, J = 13.1, 8.8 Hz, 1H), 2.39 (d, J = 3.0 Hz, 6H), 2.74 (d, J = 10.9Hz, 1H), 2.88 (d, J = 10.9 Hz, 1H), 3.52 (dt, J = 22.1, 6.1 Hz, 4H),3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 4.87 (s,9H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.81 (q, J = 6.6 Hz, 1H),7.23 (s, 1H), 7.42 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 1.9Hz, 1H), 7.71 (dd, J = 8.1, 1.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 8.00(d, J = 2.4 Hz, 1H) 63ge ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J =7.0 Hz, 1H), 1.26 (m, 5H), 1.50 (dt, J = 10.5, 5.4 Hz, 4H), 1.73 (dd, J= 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.29 (d, J = 1.9Hz, 3H), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz,1H), 3.52 (m, 4H), 3.81 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1,1.6 Hz, 2H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6Hz, 1H), 7.37 (m, 3H), 7.63 (d, J = 1.9 Hz, 1H), 7.76 (m, 2H), 7.98 (d,J = 2.4 Hz, 1H) 63gf ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.08 (m, 1H), 1.26(m, 4H), 1.36 (s, 9H), 1.51 (dt, J = 10.5, 5.5 Hz, 5H), 1.74 (dd, J =13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.74(d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 23.0, 6.0Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H),5.74 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.76 (q, J = 6.6 Hz, 1H), 7.43(m, 3H), 7.61 (d, J = 1.9 Hz, 1H), 7.73 (m, 3H), 7.99 (d, J = 2.4 Hz,1H) 63gg ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.3 Hz, 6H), 1.50(dt, J = 10.5, 5.6 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J= 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J= 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd,J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.82 (q, J= 6.6 Hz, 1H), 7.41 (m, 2H), 7.61 (m, 2H), 7.74 (m, 3H), 8.00 (d, J =2.4 Hz, 1H) 63gh ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz,3H), 1.51 (dt, J = 10.4, 5.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H),2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.84 (m, 2H), 3.52 (ddq,J = 25.3, 13.2, 7.1, 5.7 Hz, 4H), 3.86 (dd, J = 8.8, 7.2 Hz, 1H), 4.18(qd, J = 7.2, 1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.82(q, J = 6.6 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H), 7.63 (m, 2H), 7.73 (dd, J= 8.3, 1.9 Hz, 1H), 7.82 (m, 2H), 8.00 (d, J = 2.3 Hz, 1H) 63gi ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.28 (m, 4H), 1.53 (dt, J = 10.2, 5.5 Hz, 4H),1.82 (dd, J = 13.2, 7.7 Hz, 1H), 2.19 (m, 1H), 2.39 (s, 3H), 2.88 (d, J= 11.2 Hz, 1H), 2.99 (d, J = 11.2 Hz, 1H), 3.55 (m, 4H), 4.02 (t, J =8.2 Hz, 1H), 4.22 (qd, J = 7.1, 1.9 Hz, 2H), 5.74 (s, 1H), 6.42 (d, J =2.3 Hz, 1H), 6.82 (m, 1H), 7.35 (dt, J = 10.4, 8.4 Hz, 1H), 7.50 (ddt, J= 7.9, 3.8, 1.8 Hz, 1H), 7.72 (m, 4H), 8.00 (d, J = 2.4 Hz, 1H) 63gj ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 3H), 1.65 (dt, J = 12.8, 6.2 Hz,4H), 2.03 (m, 1H), 2.43 (m, 4H), 3.27 (s, 2H), 3.65 (m, 4H), 4.31 (qd, J= 7.1, 2.2 Hz, 2H), 4.58 (t, J = 8.8 Hz, 1H), 4.85 (m, 1H), 6.43 (d, J =2.5 Hz, 1H), 6.89 (q, J = 6.4 Hz, 1H), 7.45 (m, 1H), 7.72 (d, J = 1.8Hz, 1H), 7.81 (m, 2H), 8.00 (m, 3H) 63gk ¹H NMR (400 MHz, MeOH-d4): δppm 1.32 (t, J = 7.1 Hz, 3H), 1.64 (q, J = 10.3, 8.1 Hz, 4H), 2.04 (dd,J = 13.6, 8.9 Hz, 1H), 2.44 (m, 4H), 2.80 (s, 1H), 3.25 (m, 2H), 3.56(m, 1H), 3.70 (d, J = 5.7 Hz, 2H), 4.32 (qd, J = 7.1, 2.5 Hz, 2H), 4.57(t, J = 8.8 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.90 (q, J = 6.5 Hz, 1H),7.76 (q, J = 1.5, 1.0 Hz, 2H), 7.85 (m, 2H), 7.95 (m, 1H), 8.04 (m, 2H)63gl ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51(dt, J = 10.3, 5.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J= 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J= 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd,J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.82 (q, J= 6.6 Hz, 1H), 7.31 (ddt, J = 8.1, 2.3, 1.1 Hz, 1H), 7.57 (dd, J = 15.9,7.9 Hz, 2H), 7.74 (m, 4H), 8.01 (d, J = 2.4 Hz, 1H) 63gm ¹H NMR (400MHz, MeOH-d4): δ ppm 1.30 (d, J = 34.9 Hz, 12H), 1.51 (dt, J = 10.4, 5.7Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (m, 1H), 2.39 (d, J = 3.3Hz, 6H), 2.74 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m,5H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.2, 1.6 Hz, 2H),4.87 (s, 3H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.8Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.46 (t, J = 1.6 Hz, 1H), 7.59 (d, J= 1.8 Hz, 1H), 7.75 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H) 63gn ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.50 (dt, J = 10.8, 5.6Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz,1H), 2.41 (d, J = 11.8 Hz, 6H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J =11.0 Hz, 1H), 3.52 (dq, J = 24.2, 7.6, 6.3 Hz, 4H), 3.81 (dd, J = 8.7,7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H), 6.41 (d, J =2.4 Hz, 1H), 6.79 (m, 1H), 7.45 (m, 2H), 7.63 (dd, J = 7.6, 2.0 Hz, 2H),7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H) 63go ¹H NMR (400 MHz, MeOH-d4): δppm 0.88 (d, J = 7.9 Hz, 1H), 1.26 (t, J = 7.1 Hz, 7H), 1.50 (dt, J =10.5, 5.6 Hz, 8H), 1.74 (dd, J = 13.1, 7.2 Hz, 2H), 2.07 (dd, J = 13.1,8.8 Hz, 2H), 2.34 (t, J = 0.6 Hz, 1H), 2.40 (d, J = 9.3 Hz, 16H), 2.75(d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 2H), 3.52 (m, 8H), 3.82 (dd,J = 8.8, 7.2 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz, 4H), 5.73 (s, 2H), 6.41(d, J = 2.3 Hz, 2H), 6.79 (q, J = 6.6 Hz, 2H), 7.44 (d, J = 0.9 Hz, 4H),7.62 (d, J = 1.8 Hz, 2H), 7.74 (m, 4H), 7.98 (d, J = 2.4 Hz, 2H) 63gp ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.27 (q, J = 7.1, 5.7 Hz, 7H), 1.51 (dt, J= 10.7, 5.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (td, J =15.3, 14.1, 7.4 Hz, 1H), 2.32 (d, J = 2.1 Hz, 3H), 2.39 (s, 2H), 2.75(d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 22.2, 6.1Hz, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (m, 2H), 5.74 (s, 1H),6.41 (d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.5 Hz, 1H), 7.10 (t, J = 9.0 Hz,1H), 7.56 (m, 3H), 7.74 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H) 63gq ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.89 (m, 1H), 1.26 (dq, J = 10.3, 5.8, 3.2 Hz,6H), 1.46 (m, 7H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (m, 1H), 2.39(s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m,4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.16 (m, 4H), 5.74 (s, 1H), 6.41(d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.5 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H),7.47 (m, 4H), 7.73 (m, 2H), 7.97 (d, J = 2.3 Hz, 1H) 63gr ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (t, J = 8.0 Hz, 5H),1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.0, 8.7 Hz, 1H), 2.40(s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 10.9 Hz, 1H), 3.25 (p,J = 1.7 Hz, 1H), 3.53 (m, 5H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.18 (qd,J = 7.1, 1.6 Hz, 2H), 4.82 (s, 1H), 5.73 (s, 1H), 6.00 (m, 1H), 6.42 (d,J = 2.4 Hz, 1H), 6.85 (d, J = 6.6 Hz, 1H), 7.48 (t, J = 1.9 Hz, 1H),7.69 (m, 3H), 7.80 (m, 3H), 8.03 (d, J = 2.4 Hz, 1H) 63gs ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (m, 10H), 1.50 (dt, J = 10.3, 5.6 Hz, 4H),1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39(s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.93 (m, 2H), 3.52 (m, 5H), 3.82(dd, J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.74 (s, 1H),6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.26 (dt, J = 7.6,1.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.47 (m, 2H), 7.61 (d, J = 1.9Hz, 1H), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H) 63gt ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 11.0, 5.6 Hz, 4H), 1.74 (dd,J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.2, 8.8 Hz, 1H), 2.40 (s, 2H),2.75 (d, J = 10.9 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.82(dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.72 (s, 1H),6.00 (m, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.5 Hz, 1H), 7.71(m, 2H), 7.82 (m, 2H), 7.92 (dd, J = 8.4, 2.3 Hz, 1H), 8.05 (dd, J =15.9, 2.3 Hz, 2H) 63gu ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1Hz, 3H), 1.51 (dt, J = 11.1, 5.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz,1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.75 (d, J = 11.0Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 22.4, 6.0 Hz, 4H),3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s,1H), 6.43 (d, J = 2.4 Hz, 1H), 6.86 (q, J = 6.6 Hz, 1H), 7.81 (m, 5H),7.97 (m, 1H), 8.03 (d, J = 2.4 Hz, 1H) 63gv ¹H NMR (400 MHz, MeOH-d4): δppm 0.08 (m, 1H), 1.26 (m, 4H), 1.51 (dt, J = 10.7, 5.5 Hz, 5H), 1.73(dd, J = 13.1, 7.2 Hz, 1H), 2.06 (m, 1H), 2.40 (s, 3H), 2.74 (d, J =11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.26 (s, 1H), 3.53 (dt, J =22.3, 6.1 Hz, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1,1.6 Hz, 2H), 5.74 (s, 1H), 6.42 (dd, J = 2.4, 0.6 Hz, 1H), 6.83 (q, J =6.6 Hz, 1H), 7.57 (dd, J = 8.1, 7.5 Hz, 1H), 7.74 (t, J = 1.1 Hz, 1H),7.87 (m, 4H), 8.00 (d, J = 2.4 Hz, 1H), 8.19 (m, 1H) 63gw ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 10.3, 5.5Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz,1H), 2.41 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H),3.53 (dt, J = 23.4, 6.0 Hz, 4H), 3.83 (dd, J = 8.8, 7.1 Hz, 1H), 4.18(qd, J = 7.2, 1.7 Hz, 2H), 5.72 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.87(q, J = 6.6 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.89 (m, 2H), 8.00 (s,1H), 8.07 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 1.5 Hz, 2H) 63gx ¹H NMR (400MHz, MeOH-d4): δ ppm 1.28 (m, 10H), 1.50 (dt, J = 10.2, 5.5 Hz, 4H),1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (m, 1H), 2.39 (s, 3H), 2.74 (d, J= 11.0 Hz, 1H), 2.88 (d, J = 10.9 Hz, 1H), 3.53 (m, 4H), 3.82 (dd, J =8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.2, 1.6 Hz, 2H), 4.65 (h, J = 5.9 Hz,1H), 5.73 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H),6.92 (m, 1H), 7.19 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 1.8Hz, 1H), 7.74 (m, 2H), 7.98 (d, J = 2.3 Hz, 1H) 63gy ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz, 4H), 1.46 (m, 7H), 1.75 (dd, J =13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.76(d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 24.9,7.0, 6.0 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (ttd, J = 7.0,5.2, 2.5 Hz, 4H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J =6.5 Hz, 1H), 7.18 (m, 2H), 7.35 (dd, J = 8.0, 2.1 Hz, 1H), 7.62 (d, J =1.8 Hz, 1H), 7.74 (m, 2H), 7.99 (d, J = 2.3 Hz, 1H) 63gz ¹H NMR (400MHz, MeOH-d4): δ ppm 1.29 (m, 9H), 1.51 (dt, J = 10.4, 5.6 Hz, 4H), 1.73(dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.7 Hz, 1H), 2.39 (s,3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H),3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 4.66 (h,J = 6.1 Hz, 1H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.70 (dt, J =10.8, 2.2 Hz, 1H), 6.81 (q, J = 6.6 Hz, 1H), 6.99 (m, 2H), 7.62 (d, J =1.8 Hz, 1H), 7.72 (dd, J = 8.3, 1.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H),8.00 (d, J = 2.3 Hz, 1H) 63ha ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29-1.40(m, 3 H), 1.55-1.76 (m, 4 H), 2.06 (br. s., 1 H), 2.35-2.54 (m, 4 H),3.29 (s, 2 H) 3.50-3.78 (m, 4H), 3.85 (s, 3H), 4.34 (dd, J = 7.03, 2.34Hz, 2 H), 4.60 (s, 1 H), 5.96 (s, 1 H), 6.44 (d, J = 2.15 Hz, 1 H), 6.81(d, J = 6.44 Hz, 1 H), 7.03 (d, J = 8.79 Hz, 2 H), 7.50-7.68 (m, 3 H),7.70-7.82 (m, 2 H), 7.97 (d, J = 2.15 Hz, 1 H) 63hb ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.34 (t, J = 7.13 Hz, 3 H), 1.43 (t, J = 7.03 Hz, 3 H),1.63-1.82 (m, 4 H), 2.01-2.14 (m, 1 H), 2.43 (s, 3 H) 2.46-2.57 (m, 1H), 3.31 (br. s., 2 H), 3.59-3.93 (m, 4 H), 4.11 (d, J = 7.03 Hz, 2 H),4.26-4.41 (m, 2 H), 4.56-4.68 (m, 1 H), 6.44 (d, J = 2.15 Hz, 1 H),6.76-6.93 (m, 1 H), 7.04 (d, J = 8.79 Hz, 2 H), 7.66 (dd, J = 5.17, 3.61Hz, 3 H), 7.72-7.85 (m, 2 H), 7.93-8.02 (m, 1 H) 63hc ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz, 3H), 1.51 (dt, J = 11.0, 5.6 Hz,4H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H),2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52(m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H),4.88 (s, 7H), 5.72 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.5Hz, 1H), 7.52 (m, 2H), 7.67 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.3, 1.9Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H) 63hd ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (dt, J = 8.1, 4.7 Hz, 4H),1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.77(d, J = 10.9 Hz, 1H), 2.91 (d, J = 10.9 Hz, 1H), 3.53 (dq, J = 16.3,6.7, 6.2 Hz, 4H), 3.65 (s, 3H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.19(qd, J = 7.2, 1.6 Hz, 2H), 5.51 (d, J = 18.6 Hz, 1H), 6.49 (dd, J = 6.9,2.0 Hz, 1H), 6.81 (q, J = 6.8 Hz, 1H), 6.91 (s, 1H), 7.35 (d, J = 2.2Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.80(d, J = 6.8 Hz, 1H) 63he ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J =7.1 Hz, 4H), 1.51 (dt, J = 10.8, 5.6 Hz, 5H), 1.74 (dd, J = 13.1, 7.1Hz, 1H), 2.07 (dd, J = 13.0, 8.7 Hz, 1H), 2.38 (d, J = 9.6 Hz, 6H), 2.74(d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 21.9, 6.3Hz, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H),4.88 (s, 15H), 5.74 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.81 (q, J = 6.6Hz, 1H), 7.33 (m, 1H), 7.58 (m, 1H), 7.66 (t, J = 2.6 Hz, 2H), 7.77 (m,2H), 7.99 (d, J = 2.4 Hz, 1H) 63hf ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.08(m, 1H), 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.76(dd, J = 13.2, 7.4 Hz, 1H), 2.11 (dd, J = 13.2, 8.8 Hz, 1H), 2.39 (s,7H), 2.79 (d, J = 11.0 Hz, 1H), 2.92 (d, J = 11.1 Hz, 1H), 3.52 (dq, J =29.5, 7.4, 6.4 Hz, 5H), 3.89 (dd, J = 8.7, 7.4 Hz, 1H), 4.19 (qd, J =7.2, 1.7 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.80 (q, J =6.6 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 7.9, 1.9 Hz, 1H),7.62 (d, J = 1.9 Hz, 1H), 7.73 (m, 3H), 7.99 (d, J = 2.4 Hz, 1H) 63hg ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dt, J =10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1,8.8 Hz, 1H), 2.40 (s, 3H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0Hz, 1H), 3.53 (m, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J =7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.86 (q, J =6.6 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 7.79 (m, 6H), 8.04 (d, J =2.4 Hz, 1H) 63hh ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.93 (m, 2H), 1.36 (m,11H), 1.69 (td, J = 13.3, 6.6 Hz, 1H), 2.04 (dd, J = 13.1, 8.8 Hz, 1H),2.39 (s, 3H), 2.72 (d, J = 11.0 Hz, 1H), 2.86 (d, J = 11.0 Hz, 1H), 3.50(m, 4H), 3.80 (t, J = 7.9 Hz, 1H), 4.17 (m, 2H), 5.71 (s, 1H), 6.42 (d,J = 2.4 Hz, 1H), 6.85 (q, J = 6.6 Hz, 1H), 7.20 (dt, J = 8.5, 2.1 Hz,1H), 7.39 (dt, J = 9.7, 2.0 Hz, 1H), 7.52 (t, J = 1.6 Hz, 1H), 7.67 (m,2H), 7.80 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H) 63hi ¹H NMR (400MHz, MeOH-d4): δ ppm 0.75 (m, 2H), 1.01 (dq, J = 8.4, 2.4 Hz, 2H), 1.19(s, 1H), 1.26 (t, J = 7.1 Hz, 4H), 1.52 (m, 4H), 1.74 (dd, J = 13.1, 7.2Hz, 1H), 2.02 (m, 2H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz,1H), 3.49 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, 1H), 4.18 (qd, J = 7.1,1.5 Hz, 2H), 5.44 (s, 1H), 6.60 (q, J = 6.9 Hz, 1H), 7.20 (m, 4H), 7.41(m, 2H), 7.66 (d, J = 8.5 Hz, 1H) 63hj ¹H NMR (400 MHz, MeOH-d4): δ ppm1.25 (t, J = 7.1 Hz, 3H), 1.35 (d, J = 6.0 Hz, 6H), 1.49 (ddd, J = 12.1,7.6, 4.8 Hz, 4H), 1.72 (dd, J = 13.1, 7.2 Hz, 1H), 2.05 (dd, J = 13.1,8.8 Hz, 1H), 2.39 (s, 3H), 2.72 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0Hz, 1H), 3.51 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J =7.1, 1.6 Hz, 2H), 4.67 (hept, J = 6.1 Hz, 1H), 5.73 (s, 1H), 6.41 (d, J= 2.4 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.54(m, 2H), 7.67 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 2.4 Hz,1H) 63hk ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (m, 4H),1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.77(d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.52 (dq, J = 27.4,7.7, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.6Hz, 2H), 5.51 (d, J = 14.8 Hz, 2H), 6.79 (q, J = 6.8 Hz, 1H), 7.40 (d, J= 2.2 Hz, 1H), 7.52 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 8.3Hz, 1H), 8.47 (s, 1H), 9.34 (s, 1H) 63hl ¹H NMR (400 MHz, MeOH-d4): δppm 1.25 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 7.8, 4.8 Hz, 4H), 1.73 (dd,J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.7 Hz, 1H), 2.74 (d, J =10.9 Hz, 1H), 2.88 (d, J = 10.9 Hz, 1H), 3.10 (s, 6H), 3.49 (m, 4H),3.81 (dd, J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.3 Hz, 2H), 5.47 (s,1H), 6.69 (m, 3H), 7.32 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 8.5, 2.2 Hz,1H), 7.68 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 5.2 Hz, 1H) 63hm ¹H NMR (400MHz, MeOH-d4): δ ppm 1.24 (t, J = 7.1 Hz, 3H), 1.45 (dt, J = 9.4, 5.7Hz, 4H), 1.70 (dd, J = 13.1, 7.2 Hz, 1H), 2.03 (dd, J = 13.1, 8.7 Hz,1H), 2.70 (d, J = 11.0 Hz, 1H), 2.85 (d, J = 11.0 Hz, 1H), 3.40 (m, 4H),3.79 (t, J = 7.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 5.45 (d, J = 17.0Hz, 1H), 6.68 (q, J = 6.8 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.44 (dd, J= 8.6, 2.2 Hz, 1H), 7.56 (m, 3H), 7.71 (d, J = 8.5 Hz, 1H), 7.94 (m, 4H)63hn ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.36 (s,9H), 1.52 (m, 4H), 1.77 (dd, J = 13.1, 7.4 Hz, 1H), 2.13 (dd, J = 13.1,8.7 Hz, 1H), 2.80 (d, J = 11.1 Hz, 1H), 2.93 (d, J = 11.1 Hz, 1H), 3.48(m, 4H), 3.91 (dd, J = 8.7, 7.4 Hz, 1H), 4.20 (qd, J = 7.2, 1.7 Hz, 2H),5.41 (s, 1H), 6.64 (q, J = 6.9 Hz, 1H), 7.27 (m, 2H), 7.44 (m, 5H), 7.69(d, J = 7.3 Hz, 1H) 63ho ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J =7.1, 2.3 Hz, 3H), 1.53 (dt, J = 13.2, 6.2 Hz, 4H), 1.74 (dt, J = 13.6,7.0 Hz, 1H), 2.09 (m, 1H), 2.75 (dd, J = 10.9, 7.2 Hz, 1H), 2.90 (dd, J= 11.0, 6.6 Hz, 1H), 3.29 (s, 1H), 3.52 (m, 4H), 3.83 (td, J = 8.2, 4.3Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.47 (m, 1H), 6.43 (dt, J = 11.2, 5.6Hz, 1H), 7.22 (m, 1H), 7.38 (m, 2H), 7.61 (dd, J = 5.0, 2.2 Hz, 1H),7.81 (m, 3H) 63hp ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz,4H), 1.51 (dt, J = 10.0, 5.2 Hz, 4H), 1.80 (m, 1H), 2.17 (dd, J = 13.3,8.8 Hz, 1H), 2.86 (d, J = 11.2 Hz, 1H), 2.97 (d, J = 11.2 Hz, 1H), 3.50(m, 4H), 4.01 (t, J = 8.2 Hz, 1H), 4.21 (qd, J = 7.1, 1.9 Hz, 2H), 5.63(s, 1H), 6.69 (q, J = 6.6 Hz, 1H), 7.30 (ddd, J = 7.9, 6.9, 0.9 Hz, 1H),7.46 (m, 2H), 7.75 (m, 4H), 8.39 (d, J = 1.0 Hz, 1H) 63hq ¹H NMR (400MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 3H), 1.36 (dd, J = 6.9, 3.7Hz, 6H), 1.50 (m, 2H), 1.73 (dd, J = 13.1, 6.7 Hz, 1H), 2.05 (dd, J =13.1, 8.8 Hz, 1H), 2.81 (d, J = 10.5 Hz, 1H), 2.94 (d, J = 10.5 Hz, 1H),3.14 (p, J = 6.9 Hz, 1H), 3.47 (dt, J = 12.2, 5.6 Hz, 4H), 3.85 (dd, J =8.8, 6.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 5.42 (s, 1H),6.53 (q, J = 6.7 Hz, 1H), 7.25 (m, 3H), 7.42 (dd, J = 8.5, 2.2 Hz, 1H),7.68 (d, J = 8.5 Hz, 1H), 8.65 (dd, J = 5.0, 0.8 Hz, 1H) 63hr ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H), 1.76(dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, 1H), 2.77 (d, J= 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.51 (dq, J = 17.7, 6.1 Hz,4H), 3.84 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H),5.50 (s, 1H), 6.60 (q, J = 6.7 Hz, 1H), 7.28 (m, 3H), 7.48 (ddd, J =25.4, 8.2, 3.7 Hz, 3H), 7.66 (d, J = 8.5 Hz, 1H) 63hs ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (m, 4H), 1.75 (dd, J =13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.50 (dq, J = 25.8, 7.7, 6.9 Hz,4H), 3.85 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.5 Hz, 2H),5.50 (s, 1H), 6.60 (q, J = 6.7 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.52(m, 6H) 63ht ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J = 7.1 Hz, 3H),1.56 (dt, J = 11.3, 5.3 Hz, 4H), 1.86 (dd, J = 13.3, 7.9 Hz, 1H), 2.25(dd, J = 13.3, 8.7 Hz, 1H), 2.44 (s, 3H), 2.96 (d, J = 11.4 Hz, 1H),3.05 (d, J = 11.3 Hz, 1H), 3.54 (m, 3H), 3.75 (s, 1H), 4.13 (t, J = 8.3Hz, 1H), 4.24 (qd, J = 7.2, 2.0 Hz, 2H), 5.48 (s, 1H), 6.64 (q, J = 6.8Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.35 (s, 4H), 7.42 (dd, J = 8.5, 2.3Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H) 63hu ¹H NMR (400 MHz, MeOH-d4): δ ppm1.24 (m, 3H), 1.49 (dt, J = 10.2, 5.7 Hz, 4H), 1.72 (m, 1H), 2.04 (m,1H), 2.41 (s, 2H), 2.72 (d, J = 10.9 Hz, 1H), 2.86 (d, J = 10.9 Hz, 1H),3.52 (m, 4H), 3.79 (dd, J = 8.8, 7.1 Hz, 1H), 4.16 (qd, J = 7.1, 1.6 Hz,2H), 5.76 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.7 Hz, 1H),7.49 (m, 2H), 7.84 (m, 7H), 8.01 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 1.9Hz, 1H) 63hv ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H),1.53 (m, 4H), 1.78 (m, 5H), 2.11 (m, 2H), 2.25 (dt, J = 7.9, 4.0 Hz,2H), 2.41 (d, J = 18.1 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J =11.0 Hz, 1H), 3.50 (dq, J = 24.8, 7.6, 6.8 Hz, 4H), 3.82 (dd, J = 8.7,7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.48 (s, 1H), 5.76 (h, J =2.0 Hz, 1H), 6.93 (q, J = 6.9 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.30(dd, J = 8.5, 2.3 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H) 63hw ¹H NMR (400MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 8.9, 5.7Hz, 4H), 1.81 (dd, J = 13.3, 7.7 Hz, 1H), 2.17 (dd, J = 13.3, 8.8 Hz,1H), 2.39 (s, 3H), 2.88 (d, J = 11.3 Hz, 1H), 2.98 (d, J = 11.3 Hz, 1H),3.53 (m, 4H), 4.04 (t, J = 8.2 Hz, 1H), 4.21 (qd, J = 7.2, 1.8 Hz, 2H),4.90 (d, J = 1.1 Hz, 5H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78(q, J = 6.6 Hz, 1H), 7.17 (t, J = 8.6 Hz, 1H), 7.40 (m, 7H), 7.62 (m,2H), 7.74 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H) 63hx ¹H NMR (400MHz, MeOH-d4): δ ppm 1.32 (m, 9H), 1.55 (dt, J = 10.7, 5.8 Hz, 4H), 1.87(dd, J = 13.3, 8.0 Hz, 1H), 2.24 (m, 4H), 2.39 (s, 3H), 2.98 (d, J =11.4 Hz, 1H), 3.06 (d, J = 11.4 Hz, 1H), 3.58 (m, 4H), 4.22 (m, 3H),4.63 (p, J = 6.0 Hz, 1H), 5.76 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.75(q, J = 6.6 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H),7.58 (d, J = 1.7 Hz, 1H), 7.71 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H) 63hy ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.04 (m, 7H), 1.26 (t, J = 7.1 Hz, 4H),1.52 (m, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.08 (m, 2H), 2.75 (d, J= 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.50 (m, 4H), 3.80 (m, 3H),4.18 (qd, J = 7.1, 1.4 Hz, 2H), 5.48 (s, 1H), 6.70 (q, J = 6.9 Hz, 1H),7.02 (m, 2H), 7.19 (s, 2H), 7.28 (d, J = 2.3 Hz, 1H), 7.42 (m, 2H), 7.66(d, J = 8.5 Hz, 1H) 63hz ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J =6.3 Hz, 9H), 1.68 (m, 4H), 2.04 (m, 1H), 2.50 (dd, J = 13.6, 8.7 Hz,1H), 3.28 (s, 2H), 3.56 (m, 5H), 4.32 (qd, J = 7.2, 2.2 Hz, 2H), 4.62(m, 2H), 6.59 (m, 1H), 6.97 (m, 2H), 7.53 (m, 9H), 7.66 (dd, J = 8.3,2.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H) 63ia ¹H NMR (400 MHz, MeOH-d4): δppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 9.7, 5.5 Hz, 4H), 1.74 (dd,J = 13.0, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J =11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.51 (dq, J = 23.9, 7.7, 6.6Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.5 Hz, 2H),5.56 (s, 1H), 6.68 (q, J = 7.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.82(m, 2H), 8.03 (dd, J = 8.9, 2.0 Hz, 1H), 8.15 (m, 3H), 8.81 (dd, J =2.9, 0.9 Hz, 1H) 63ib ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4Hz, 3H), 1.24 (m, 3H), 1.50 (dt, J = 10.7, 5.6 Hz, 4H), 1.79 (m, 3H),2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz,1H), 2.87 (m, 1H), 3.55 (m, 5H), 3.81 (dd, J = 8.8, 7.2 Hz, 1H), 4.04(t, J = 6.4 Hz, 2H), 4.17 (qd, J = 7.2, 1.7 Hz, 2H), 5.75 (s, 1H), 6.41(d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H),7.45 (m, 2H), 7.60 (d, J = 1.8 Hz, 1H), 7.73 (m, 2H), 7.98 (d, J = 2.4Hz, 1H) 63ic ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.00 (t, J = 7.4 Hz, 3H),1.26 (t, J = 7.1 Hz, 3H), 1.51 (m, 6H), 1.76 (m, 3H), 2.07 (dd, J =13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J =11.0 Hz, 1H), 3.53 (qd, J = 13.9, 7.7 Hz, 4H), 3.81 (dd, J = 8.7, 7.2Hz, 1H), 4.14 (m, 4H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q,J = 6.6 Hz, 1H), 7.15 (m, 1H), 7.46 (m, 2H), 7.61 (d, J = 1.7 Hz, 1H),7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H) 63id ¹H NMR (400 MHz, MeOH-d4): δppm 1.25 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.73 (dd, J = 13.1, 7.2 Hz,1H), 2.07 (dd, J = 13.0, 8.8 Hz, 1H), 2.40 (s, 3H), 2.64 (s, 3H), 2.74(d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.81 (dd,J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, 1H), 6.44(d, J = 2.3 Hz, 1H), 6.86 (q, J = 6.6 Hz, 1H), 7.76 (m, 3H), 7.85 (d, J= 1.2 Hz, 2H), 8.08 (m, 2H) 63ie ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89(d, J = 6.7 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H), 1.72 (ddd,J = 23.9, 13.2, 7.0 Hz, 1H), 1.94 (m, 4H), 2.11 (dd, J = 13.1, 8.8 Hz,1H), 2.77 (d, J = 10.9 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.55 (m, 9H),3.85 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.53 (s,1H), 6.69 (q, J = 6.7 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.48 (m, 2H),7.64 (m, 3H), 7.93 (s, 1H) 63if ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27(td, J = 7.1, 0.8 Hz, 4H), 1.53 (m, 4H), 1.76 (m, 9H), 1.97 (dd, J =13.4, 6.8 Hz, 2H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 11.0Hz, 1H), 2.91 (d, J = 10.9 Hz, 1H), 3.31 (m, 3H), 3.51 (dq, J = 19.6,6.3 Hz, 4H), 3.84 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (m, 2H), 5.48 (s, 1H),6.71 (q, J = 6.9 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 7.02 (dd, J = 8.4,2.6 Hz, 1H), 7.18 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.43 (m, 2H), 7.66(d, J = 8.5 Hz, 1H) 63ig ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (dd, J =6.7, 0.7 Hz, 1H), 1.27 (td, J = 7.1, 0.7 Hz, 3H), 1.53 (m, 4H), 1.75(dd, J = 13.1, 7.3 Hz, 1H), 2.11 (m, 1H), 2.76 (d, J = 11.0 Hz, 1H),2.90 (d, J = 11.0 Hz, 1H), 3.30 (dq, J = 3.5, 1.8 Hz, 5H), 3.54 (m,10H), 3.82 (m, 5H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 6.70(q, J = 6.7 Hz, 1H), 6.84 (m, 1H), 7.30 (m, 1H), 7.51 (m, 3H), 7.66 (m,2H), 7.79 (s, 1H) 63ih ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.39 (m, 12H),1.84 (dd, J = 13.2, 7.8 Hz, 1H), 1.98 (m, 5H), 2.24 (m, 1H), 2.92 (d, J= 11.3 Hz, 1H), 3.02 (d, J = 11.2 Hz, 1H), 3.54 (ddq, J = 27.6, 15.0,7.8, 7.4 Hz, 6H), 3.89 (s, 1H), 4.07 (t, J = 8.2 Hz, 1H), 4.23 (qd, J =7.1, 2.0 Hz, 2H), 4.93 (d, J = 1.4 Hz, 11H), 5.55 (s, 1H), 6.63 (q, J =6.7 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H),7.63 (m, 3H), 7.89 (dt, J = 7.7, 1.6 Hz, 1H), 8.35 (s, 1H) 63ii ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.27 (td, J = 7.4, 5.4 Hz, 7H), 1.52 (dt, J =7.6, 4.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1,8.7 Hz, 1H), 2.74 (m, 3H), 2.90 (d, J = 11.0 Hz, 1H), 3.30 (d, J = 9.9Hz, 1H), 3.49 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J =7.1, 1.5 Hz, 2H), 5.46 (s, 1H), 6.64 (q, J = 6.8 Hz, 1H), 7.30 (m, 4H),7.43 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H) 63ij ¹H NMR (400 MHz, MeOH-d4): δppm 1.30 (dd, J = 6.9, 5.1 Hz, 6H), 1.59 (d, J = 5.6 Hz, 4H), 2.03 (dd,J = 13.4, 7.2 Hz, 1H), 2.30 (dd, J = 13.4, 9.2 Hz, 1H), 3.03 (m, 2H),3.22 (d, J = 11.7 Hz, 1H), 3.46 (tt, J = 16.4, 7.0 Hz, 2H), 3.62 (q, J =8.5 Hz, 2H), 4.05 (dd, J = 9.1, 7.1 Hz, 1H), 5.48 (s, 1H), 6.62 (q, J =6.7 Hz, 1H), 7.31 (m, 4H), 7.44 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H) 63ik¹H NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (td, J =7.2, 0.6 Hz, 4H), 1.51 (dt, J = 10.0, 5.7 Hz, 4H), 1.77 (ddd, J = 27.5,13.6, 7.1 Hz, 3H), 2.08 (dd, J = 13.1, 8.7 Hz, 1H), 2.74 (d, J = 11.0Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.30 (p, J = 1.6 Hz, 5H), 3.51 (m,4H), 3.81 (dd, J = 8.7, 7.2 Hz, 1H), 3.95 (t, J = 6.5 Hz, 2H), 4.18 (qd,J = 7.1, 1.5 Hz, 2H), 5.53 (s, 1H), 6.61 (q, J = 7.2 Hz, 1H), 6.97 (m,2H), 7.56 (m, 6H) 63il ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1Hz, 4H), 1.46 (m, 8H), 1.73 (dd, J = 13.0, 7.3 Hz, 1H), 2.08 (m, 1H),2.74 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.02 (m, 2H), 3.50(dd, J = 17.6, 11.2 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J= 7.2, 1.5 Hz, 2H), 5.53 (s, 1H), 6.99 (q, J = 6.9 Hz, 1H), 7.67 (m,3H), 8.03 (dd, J = 8.9, 2.1 Hz, 1H), 8.14 (m, 3H), 8.80 (dd, J = 2.8,0.9 Hz, 1H) 63im ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz,5H), 1.53 (td, J = 7.3, 6.9, 4.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz,1H), 2.10 (m, 1H), 2.29 (s, 3H), 2.39 (s, 3H), 2.53 (s, 2H), 2.76 (d, J= 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52 (m, 6H), 3.83 (m, 3H),4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (d, J = 15.3 Hz, 1H), 6.71 (q, J =6.6 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.50 (m, 3H), 7.66 (m, 2H), 7.80(s, 1H) 63in ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (m, 4H), 1.54 (m,4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 12.8, 8.5 Hz, 1H),2.66 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.52(dd, J = 14.8, 8.9 Hz, 5H), 3.83 (dd, J = 8.7, 7.3 Hz, 1H), 4.18 (qd, J= 7.1, 1.6 Hz, 2H), 5.54 (s, 1H), 6.85 (t, J = 7.0 Hz, 1H), 7.65 (d, J =2.9 Hz, 3H), 8.04 (dd, J = 8.9, 2.0 Hz, 1H), 8.15 (m, 3H), 8.81 (d, J =2.8 Hz, 1H) 63io ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.15 (t, J = 7.0 Hz,3H), 1.26 (t, J = 7.1 Hz, 6H), 1.53 (dt, J = 10.1, 5.5 Hz, 4H), 1.75(dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J= 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.36 (d, J = 7.7 Hz, 1H),3.54 (m, 6H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.6 Hz,2H), 5.55 (s, 1H), 6.65 (q, J = 7.1 Hz, 1H), 7.46 (m, 2H), 7.62 (d, J =8.1 Hz, 2H), 7.72 (m, 4H) 63ip ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26(td, J = 7.1, 1.0 Hz, 7H), 1.53 (m, 8H), 1.74 (dd, J = 13.1, 7.2 Hz,2H), 2.09 (dd, J = 13.1, 8.7 Hz, 2H), 2.75 (d, J = 11.0 Hz, 2H), 2.89(d, J = 11.0 Hz, 2H), 3.28 (d, J = 14.7 Hz, 1H), 3.53 (m, 9H), 3.82 (dd,J = 8.7, 7.2 Hz, 2H), 4.18 (qd, J = 7.1, 1.5 Hz, 4H), 5.55 (s, 2H), 6.66(q, J = 7.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 4H), 7.72 (m, 8H), 7.95 (m,4H) 63iq ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 6H), 1.54 (m, 4H),1.78 (dd, J = 13.1, 7.4 Hz, 1H), 2.14 (dd, J = 13.2, 8.8 Hz, 1H), 2.81(d, J = 13.9 Hz, 4H), 2.94 (d, J = 11.0 Hz, 1H), 3.22 (s, 2H), 3.52(ddt, J = 19.7, 11.9, 6.0 Hz, 4H), 3.92 (t, J = 8.0 Hz, 1H), 4.21 (qd, J= 7.8, 6.4, 4.7 Hz, 2H), 4.88 (s, 1H), 5.51 (s, 1H), 6.75 (q, J = 6.7Hz, 1H), 7.49 (m, 2H), 7.72 (m, 2H) 63ir ¹H NMR (400 MHz, MeOH-d4): δppm 1.04 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H),1.76 (ddd, J = 25.2, 13.5, 7.1 Hz, 3H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H),2.74 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.47 (dq, J =26.7, 7.9, 6.9 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 3.95 (t, J = 6.5Hz, 2H), 4.18 (m, 2H), 5.45 (s, 1H), 6.66 (q, J = 6.9 Hz, 1H), 6.97 (m,2H), 7.55 (m, 9H), 7.73 (d, J = 8.3 Hz, 1H) 63is ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.81 (dd, J =13.2, 7.6 Hz, 1H), 2.18 (dd, J = 13.3, 8.8 Hz, 1H), 2.87 (d, J = 11.2Hz, 1H), 2.98 (d, J = 11.1 Hz, 1H), 3.51 (m, 4H), 4.00 (t, J = 8.1 Hz,1H), 4.21 (qd, J = 7.1, 1.8 Hz, 2H), 5.49 (d, J = 2.0 Hz, 1H), 6.82 (q,J = 6.7 Hz, 1H), 7.13 (m, 2H), 7.46 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H)63it ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53(dt, J = 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.0, 7.2 Hz, 1H), 2.10 (dd, J= 13.1, 8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz,1H), 3.15 (s, 3H), 3.53 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.18(qd, J = 7.1, 1.6 Hz, 2H), 5.56 (s, 1H), 6.67 (q, J = 7.1 Hz, 1H), 7.66(d, J = 8.2 Hz, 2H), 7.74 (m, 2H), 7.89 (m, 2H), 8.02 (m, 2H) 63iu ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dt, J =10.8, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1,8.8 Hz, 1H), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0Hz, 1H), 3.15 (s, 3H), 3.53 (m, 4H), 3.81 (dd, J = 8.8, 7.2 Hz, 1H),4.18 (qd, J = 7.2, 1.7 Hz, 2H), 5.74 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H),6.85 (q, J = 6.6 Hz, 1H), 7.76 (dd, J = 1.7, 0.6 Hz, 1H), 7.83 (m, 2H),7.95 (m, 2H), 8.03 (m, 3H) 63iv ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.05(t, J = 7.4 Hz, 3H), 1.26 (m, 3H), 1.49 (dt, J = 10.7, 5.7 Hz, 4H), 1.78(m, 3H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.25 (d, J = 14.0 Hz, 1H),2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53(m, 4H), 3.83 (t, J = 8.0 Hz, 1H), 3.95 (t, J = 6.4 Hz, 2H), 4.18 (qd, J= 7.1, 1.6 Hz, 2H), 5.76 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.75 (t, J =6.7 Hz, 1H), 6.98 (m, 2H), 7.58 (m, 3H), 7.71 (m, 2H), 7.96 (d, J = 2.4Hz, 1H) 63ix ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.14 (t, J = 7.0 Hz, 3H),1.26 (t, J = 7.1 Hz, 7H), 1.51 (dt, J = 10.8, 5.7 Hz, 4H), 1.73 (dd, J =13.0, 7.2 Hz, 1H), 2.08 (dd, J = 13.0, 8.8 Hz, 1H), 2.39 (d, J = 1.7 Hz,3H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.31 (d, J =16.3 Hz, 3H), 3.56 (s, 6H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.18 (m,2H), 5.75 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.5 Hz, 1H),7.47 (dd, J = 8.3, 2.0 Hz, 2H), 7.70 (d, J = 1.8 Hz, 1H), 7.79 (m, 4H),8.01 (d, J = 2.4 Hz, 1H) 63iy ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t,J = 7.1 Hz, 5H), 1.53 (dt, J = 9.7, 5.4 Hz, 8H), 1.74 (dd, J = 13.0, 7.3Hz, 2H), 2.09 (dd, J = 13.1, 8.8 Hz, 2H), 2.76 (d, J = 11.0 Hz, 2H),2.91 (d, J = 19.4 Hz, 7H), 3.36 (s, 1H), 3.53 (m, 8H), 3.83 (dd, J =8.7, 7.2 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz, 4H), 4.97 (s, 1H), 5.55 (s,2H), 6.65 (q, J = 7.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 4H), 7.71 (m, 7H),7.89 (m, 4H) 63iz ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz,4H), 1.51 (dt, J = 10.6, 5.5 Hz, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H),2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.78 (d, J = 11.1 Hz,1H), 2.91 (d, J = 11.0 Hz, 1H), 3.54 (qq, J = 14.0, 7.5, 6.5 Hz, 4H),3.88 (dd, J = 8.7, 7.4 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.75 (s,1H), 6.43 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.73 (d, J =1.6 Hz, 1H), 7.84 (m, 4H), 7.99 (m, 3H) 63ja ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.27 (m, 7H), 1.53 (dt, J = 9.9, 5.5 Hz, 8H), 1.77 (dd, J = 13.1,7.4 Hz, 2H), 2.17 (m, 2H), 2.81 (d, J = 11.1 Hz, 2H), 2.93 (d, J = 11.1Hz, 2H), 3.33 (d, J = 12.6 Hz, 1H), 3.52 (ddt, J = 17.5, 11.5, 5.2 Hz,8H), 3.90 (dd, J = 8.6, 7.5 Hz, 2H), 4.20 (qd, J = 7.2, 1.7 Hz, 3H),5.56 (s, 2H), 6.66 (q, J = 7.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 4H), 7.71(d, J = 8.3 Hz, 4H), 7.79 (m, 4H), 7.96 (m, 4H) 63jb ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 5H), 1.53 (dt, J = 9.6, 5.3 Hz,5H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.7 Hz, 1H),2.61 (m, 7H), 2.77 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.56(m, 8H), 3.71 (t, J = 4.7 Hz, 5H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.19(qd, J = 7.1, 1.6 Hz, 2H), 5.55 (s, 1H), 6.66 (q, J = 7.2 Hz, 1H), 7.63(d, J = 8.1 Hz, 2H), 7.73 (m, 4H), 7.91 (m, 2H) 63jc ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.21 (dt, J = 33.8, 7.2 Hz, 4H), 1.51 (dt, J = 10.8, 5.4Hz, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.08 (m, 1H), 2.40 (s, 3H),2.58 (dt, J = 23.6, 5.8 Hz, 6H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (dd, J= 11.0, 5.9 Hz, 1H), 3.32 (s, 1H), 3.57 (m, 6H), 3.70 (t, J = 4.7 Hz,4H), 3.82 (m, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.75 (s, 1H), 6.43(d, J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H),7.81 (m, 4H), 7.96 (m, 4H) 63jd ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26(td, J = 7.1, 1.3 Hz, 3H), 1.52 (dt, J = 9.5, 5.5 Hz, 4H), 1.74 (dd, J =13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J = 11.1Hz, 1H), 2.89 (d, J = 10.9 Hz, 1H), 3.04 (d, J = 1.3 Hz, 3H), 3.11 (s,3H), 3.52 (m, 4H), 3.82 (m, 1H), 4.18 (qt, J = 7.1, 1.4 Hz, 2H), 5.55(d, J = 1.3 Hz, 1H), 6.66 (q, J = 7.1 Hz, 1H), 7.51 (m, 2H), 7.68 (m,6H) 63je ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.53(dt, J = 9.5, 5.3 Hz, 4H), 1.75 (dd, J = 13.0, 7.3 Hz, 1H), 2.11 (dd, J= 13.1, 8.8 Hz, 1H), 2.78 (t, J = 9.8 Hz, 3H), 2.91 (d, J = 11.0 Hz,4H), 3.50 (m, 7H), 3.75 (s, 2H), 3.85 (dd, J = 8.8, 7.3 Hz, 1H), 4.19(qd, J = 7.2, 1.6 Hz, 2H), 5.55 (s, 1H), 6.66 (q, J = 7.0 Hz, 1H), 7.51(m, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.72 (m, 4H) 63jf ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.26 (td, J = 7.4, 1.9 Hz, 8H), 1.50 (dt, J = 10.8, 5.8Hz, 5H), 1.75 (dd, J = 13.1, 7.4 Hz, 1H), 2.10 (dd, J = 13.2, 8.9 Hz,1H), 2.39 (s, 3H), 2.86 (m, 8H), 3.26 (s, 1H), 3.52 (m, 8H), 3.76 (s,2H), 3.88 (dd, J = 8.8, 7.3 Hz, 1H), 4.18 (ddtd, J = 7.7, 5.3, 3.6, 2.0Hz, 2H), 4.93 (s, 2H), 5.74 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82 (q,J = 6.6 Hz, 1H), 7.51 (dd, J = 8.3, 2.0 Hz, 2H), 7.75 (m, 7H), 8.01 (d,J = 2.4 Hz, 1H) 63jg ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (t, J = 7.2Hz, 8H), 1.57 (s, 10H), 1.95 (dd, J = 13.4, 8.4 Hz, 2H), 2.37 (t, J =11.1 Hz, 2H), 3.12 (m, 4H), 3.61 (m, 15H), 4.31 (m, 6H), 5.49 (s, 1H),5.62 (s, 1H), 6.25 (d, J = 6.9 Hz, 2H), 6.50 (t, J = 6.8 Hz, 2H), 7.31(d, J = 2.2 Hz, 2H), 7.46 (dd, J = 15.4, 7.7 Hz, 4H), 7.65 (d, J = 8.5Hz, 2H), 7.79 (d, J = 7.1 Hz, 2H) 63jh ¹H NMR (400 MHz, MeOH-d4): δ ppm1.26 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.4, 5.5 Hz, 4H), 1.74 (dd, J =13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.75(d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.83 (m,1H), 3.90 (s, 3H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.75 (s, 1H), 6.41(d, J = 2.4 Hz, 1H), 6.78 (q, J = 6.7 Hz, 1H), 7.17 (t, J = 8.9 Hz, 1H),7.48 (m, 2H), 7.61 (d, J = 1.8 Hz, 1H), 7.73 (m, 2H), 7.99 (d, J = 2.4Hz, 1H) 63ji ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 11.1 Hz, 1H),1.51 (q, J = 6.8, 6.0 Hz, 4H), 1.78 (dd, J = 13.0, 7.0 Hz, 1H), 1.89 (s,2H), 2.07 (dd, J = 13.1, 9.1 Hz, 1H), 2.40 (s, 3H), 2.68 (d, J = 11.1Hz, 1H), 2.95 (d, J = 11.1 Hz, 1H), 3.03 (s, 3H), 3.11 (s, 3H), 3.22 (s,2H), 3.45 (m, 3H), 3.63 (q, J = 7.9, 7.5 Hz, 3H), 5.75 (s, 1H), 6.43 (d,J = 2.4 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H),7.70 (m, 1H), 7.80 (m, 4H), 8.01 (d, J = 2.5 Hz, 1H) 63jj ¹H NMR (400MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4 Hz, 4H), 1.30 (t, J = 7.1 Hz, 3H),1.57 (m, 4H), 1.86 (m, 3H), 2.30 (m, 1H), 3.09 (m, 3H), 3.54 (m, 4H),4.03 (t, J = 6.4 Hz, 2H), 4.27 (m, 3H), 5.55 (s, 1H), 6.64 (q, J = 7.2Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 7.37 (m, 2H), 7.58 (q, J = 8.4 Hz,4H) 63jk ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.50(dt, J = 10.2, 5.2 Hz, 4H), 1.75 (dd, J = 13.1, 7.4 Hz, 1H), 2.10 (dd, J= 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.78 (d, J = 11.1 Hz, 1H), 2.91 (d, J= 13.6 Hz, 4H), 3.52 (m, 4H), 3.88 (dd, J = 8.7, 7.3 Hz, 1H), 4.18 (qd,J = 7.1, 1.6 Hz, 2H), 5.75 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.82 (q, J= 6.5 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.78 (m, 4H), 7.90 (m, 2H),8.01 (d, J = 2.4 Hz, 1H) 63jl ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (m,5H), 1.54 (dt, J = 11.2, 6.0 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H),2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.58 (s, 3H), 2.77 (d, J = 11.0 Hz,1H), 2.91 (d, J = 11.0 Hz, 1H), 3.55 (h, J = 7.5 Hz, 4H), 3.84 (dd, J =8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.58 (s, 1H), 6.65 (q,J = 6.6 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.5, 2.3 Hz,1H), 7.73 (m, 3H), 7.94 (ddd, J = 7.9, 1.8, 1.1 Hz, 1H), 8.32 (s, 1H)63jm ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54(dt, J = 8.6, 4.8 Hz, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, 1H), 2.11 (dd, J= 13.1, 8.8 Hz, 1H), 2.73 (s, 7H), 2.91 (d, J = 10.9 Hz, 1H), 3.55 (dp,J = 20.2, 7.2, 6.0 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J= 7.1, 1.6 Hz, 2H), 5.59 (s, 1H), 6.69 (q, J = 6.4 Hz, 1H), 7.36 (d, J =2.2 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.70 (dd, J = 13.1, 8.0 Hz,2H), 7.85 (m, 2H), 8.34 (s, 1H) 63jn ¹H NMR (400 MHz, MeOH-d4): δ ppm1.30 (m, 10H), 1.52 (dt, J = 10.2, 5.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.3Hz, 1H), 2.08 (m, 1H), 2.83 (m, 4H), 3.20 (ddd, J = 11.9, 6.2, 3.0 Hz,2H), 3.31 (s, 1H), 3.49 (ddd, J = 30.2, 13.4, 6.0 Hz, 4H), 3.90 (dddd, J= 32.2, 15.9, 7.4, 5.0 Hz, 5H), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 4.64 (p,J = 6.0 Hz, 1H), 5.52 (s, 1H), 6.96 (m, 2H), 7.40 (m, 2H), 7.54 (m, 4H)63jo ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (dt, J = 7.6,4.8 Hz, 5H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.8Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.92 (d, J = 18.5 Hz, 4H), 3.53 (m,4H), 3.85 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H),4.93 (s, 7H), 5.52 (d, J = 19.1 Hz, 1H), 6.63 (q, J = 6.7 Hz, 1H), 7.29(d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.62 (m, 3H), 7.88(dt, J = 7.7, 1.6 Hz, 1H), 8.37 (s, 1H) 63jp ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53 (dt, J = 7.7, 4.7 Hz, 4H), 1.75(dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J= 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.06 (s, 3H), 3.12 (s, 3H),3.51 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz,2H), 5.53 (s, 1H), 6.70 (q, J = 6.7 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H),7.56 (m, 5H), 7.79 (s, 1H) 63jq ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26(t, J = 7.1 Hz, 5H), 1.46 (m, 7H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.09(dd, J = 13.1, 8.7 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0Hz, 1H), 3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.15 (m, 4H),5.53 (s, 1H), 6.62 (q, J = 7.1 Hz, 1H), 7.12 (t, J = 8.7 Hz, 1H), 7.38(m, 2H), 7.58 (q, J = 8.4 Hz, 4H) 63jr ¹H NMR (400 MHz, MeOH-d4): δ ppm1.26 (t, J = 7.1 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 1.51 (m, 4H), 1.73(dd, J = 13.1, 7.3 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.74 (d, J= 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.49 (dtt, J = 19.6, 13.1,6.9 Hz, 4H), 3.82 (dd, J = 8.8, 7.3 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H),4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.53 (s, 1H), 6.61 (q, J = 7.1 Hz, 1H),6.96 (m, 2H), 7.55 (m, 6H) 63js ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26(t, J = 7.1 Hz, 3H), 1.52 (m, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10(dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0Hz, 1H), 3.16 (s, 3H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.3 Hz, 1H),4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.53 (s, 1H), 6.75 (q, J = 6.7 Hz, 1H),7.56 (m, 5H), 7.84 (d, J = 1.9 Hz, 1H), 7.99 (m, 2H) 63jt ¹H NMR (400MHz, MeOH-d4): δ ppm 1.13 (t, J = 7.2 Hz, 3H), 1.27 (q, J = 6.8 Hz, 7H),1.55 (m, 4H), 1.81 (dd, J = 13.2, 7.6 Hz, 1H), 2.18 (dd, J = 13.2, 8.7Hz, 1H), 2.86 (d, J = 11.2 Hz, 1H), 2.98 (d, J = 11.2 Hz, 1H), 3.36 (q,J = 7.1 Hz, 2H), 3.56 (m, 6H), 3.98 (t, J = 8.1 Hz, 1H), 4.21 (qd, J =7.2, 1.8 Hz, 2H), 5.54 (s, 1H), 6.74 (q, J = 6.8 Hz, 1H), 7.32 (d, J =2.2 Hz, 1H), 7.49 (m, 3H), 7.65 (m, 3H) 63ju ¹H NMR (400 MHz, MeOH-d4):δ ppm 1.04 (dd, J = 6.8, 1.9 Hz, 6H), 1.26 (t, J = 7.2 Hz, 3H), 1.50(dt, J = 10.7, 5.7 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (ddd,J = 13.0, 7.7, 4.9 Hz, 2H), 2.39 (s, 2H), 2.74 (d, J = 10.9 Hz, 1H),2.88 (d, J = 11.0 Hz, 1H), 3.49 (d, J = 7.5 Hz, 1H), 3.56 (d, J = 7.9Hz, 3H), 3.78 (m, 3H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.75 (s, 1H),6.41 (d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.6 Hz, 1H), 6.99 (m, 2H), 7.60(dd, J = 8.7, 1.9 Hz, 3H), 7.72 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H) 63jv¹H NMR (400 MHz, MeOH-d4): δ ppm 1.04 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H),1.48 (dt, J = 10.6, 5.7 Hz, 4H), 1.71 (dd, J = 13.1, 7.2 Hz, 1H), 2.05(dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.72 (d, J = 11.0 Hz, 1H),2.86 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.64 (s, 2H), 3.80 (dd, J =8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.75 (s, 1H), 6.41 (d,J = 2.3 Hz, 1H), 6.76 (q, J = 6.6 Hz, 1H), 6.98 (m, 2H), 7.57 (m, 3H),7.70 (m, 2H), 7.96 (d, J = 2.4 Hz, 1H) 63jw ¹H NMR (400 MHz, MeOH-d4): δppm 1H NMR (MeOH-d4) δ: 1.29 (t, J = 7.1 Hz, 7H), 1.53 (s, 8H), 1.79 (s,2H), 2.14 (s, 2H), 2.81 (s, 2H), 2.94 (d, J = 10.8 Hz, 2H), 3.50 (s,7H), 3.57 (s, 2H), 3.90 (t, J = 8.0 Hz, 2H), 4.22 (qd, J = 7.1, 1.7 Hz,3H), 5.43 (s, 1H), 6.51 (s, 1H), 6.85 (s, 1H), 7.25 (s, 1H), 7.48 (d, J= 9.7 Hz, 4H), 7.55 (d, J = 7.5 Hz, 2H), 7.79 (s, 4H), 8.13 (s, 2H) 63jx¹H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.49 (dt, J =10.8, 5.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.03 (m, 3H), 2.39(s, 3H), 2.73 (d, J = 11.0 Hz, 1H), 2.85 (m, 3H), 3.53 (m, 4H), 3.81(dd, J = 8.7, 7.1 Hz, 1H), 4.17 (m, 4H), 5.75 (s, 1H), 6.40 (d, J = 2.3Hz, 1H), 6.77 (dd, J = 17.0, 7.9 Hz, 2H), 7.36 (dq, J = 4.4, 2.5 Hz,2H), 7.56 (d, J = 1.8 Hz, 1H), 7.69 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H)63jy ¹H NMR (400 MHz, MeOH-d4): δ 1.27 (dd, J = 7.9, 6.4 Hz, 4H), 1.54(dt, J = 10.7, 5.6 Hz, 4H), 1.76 (dd, J = 13.2, 7.4 Hz, 1H), 2.12 (dd, J= 13.1, 8.8 Hz, 1H), 2.78 (m, 3H), 2.92 (m, 3H), 3.53 (m, 6H), 3.76 (s,2H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H),5.51 (d, J = 15.6 Hz, 1H), 6.72 (q, J = 6.6 Hz, 1H), 7.33 (d, J = 2.2Hz, 1H), 7.51 (m, 3H), 7.66 (m, 2H), 7.79 (s, 1H) 63jz ¹H NMR (400 MHz,MeOH-d4): δ 0.46 (m, 4H), 1.27 (m, 4H), 1.53 (dt, J = 11.2, 5.6 Hz, 4H),1.72 (m, 2H), 2.13 (dd, J = 13.1, 8.8 Hz, 1H), 2.58 (s, 2H), 2.73 (s,2H), 2.80 (d, J = 11.1 Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 3.52 (ddd, J= 25.7, 12.3, 6.8 Hz, 6H), 3.76 (s, 2H), 3.89 (dd, J = 8.7, 7.3 Hz, 1H),4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.52 (d, J = 17.0 Hz, 1H), 6.71 (q, J =6.7 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.57 (m, 5H), 7.80 (s, 1H) 63ka¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.50 (dt, J =10.3, 5.3 Hz, 4H), 1.73 (dd, J = 13.1, 7.3 Hz, 1H), 2.07 (dd, J = 13.1,8.8 Hz, 1H), 2.41 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0Hz, 1H), 3.51 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, 1H), 4.17 (qd, J =7.1, 1.6 Hz, 2H), 5.76 (s, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.88 (q, J =6.6 Hz, 1H), 7.92 (m, 3H), 8.07 (d, J = 2.4 Hz, 1H), 8.29 (m, 3H), 8.52(d, J = 8.9 Hz, 1H), 9.32 (d, J = 5.9 Hz, 1H) 63kb ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.35 (t, J = 7.22 Hz, 3 H) 1.65-1.91 (m, 4 H) 2.12 (dd,J = 13.67, 8.79 Hz, 1 H) 2.53 (dd, J = 13.67, 8.79 Hz, 1 H) 3.35 (s, 2H) 3.56-3.91 (m, 4 H) 4.35 (qd, J = 7.06, 3.03 Hz, 2 H) 4.65 (t, J =8.69 Hz, 1 H) 6.66 (d, J = 5.66 Hz, 1 H) 7.02 (d, J = 2.34 Hz, 1H)7.69-7.78 (m, 2 H) 7.79-7.88 (m, 1 H) 8.29 (d, J = 1.37 Hz, 1 H) 63kc ¹HNMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 3 H)1.40 (s, 9 H)1.64-1.85 (m, 4 H) 2.03-2.18 (m, 1 H) 2.43-2.61 (m, 1H) 3.53-3.87 (m, 4H) 4.27-4.43 (m, 2 H) 4.56-4.70 (m, 1 H) 5.51 (s, 1 H) 6.56 (d, J = 2.34Hz, 1 H) 7.30-7.42 (m, 1 H) 7.53-7.61 (m, 1 H) 7.69 (d, J = 1.95 Hz, 2H) 8.01 (d, J = 2.54 Hz, 1 H) 63kd ¹H NMR (400 MHz, MeOH-d4): δ ppm1.22-1.42 (m, 9 H) 1.51-1.72 (m, 4 H) 1.90-2.09 (m, 1 H) 2.33-2.52 (m, 1H) 3.09 (s, 1 H) 3.21 (d, J = 4.69 Hz, 2 H) 3.40-3.72 (m, 4 H) 4.31 (dd,J = 7.13, 2.25 Hz, 2 H) 4.48 (s, 1 H) 5.64 (s, 1 H) 6.47 (d, J = 2.34Hz, 1 H) 7.02 (d, J = 6.64 Hz, 1 H) 7.43-7.60 (m, 2 H) 7.72 (d, J = 8.59Hz, 1 H) 7.95 (d, J = 2.34 Hz, 1 H) 63ke ¹H NMR (400 MHz, MeOH-d4): δppm 0.68-0.95 (m, 2 H) 1.05 (dd, J = 8.40, 2.15 Hz, 2 H) 1.35 (t, J =7.13 Hz, 4 H) 1.63-1.89 (m, 4 H) 1.98-2.18 (m, 2 H) 2.44-2.63 (m, 1 H)3.78 (d, J = 5.08 Hz, 4 H) 4.35 (d, J = 7.03 Hz, 2 H) 4.63 (s, 1 H) 6.31(d, J = 2.34 Hz, 1 H) 7.09 (d, J = 6.25 Hz, 1 H) 7.51-7.67 (m, 2 H) 7.73(d, J = 8.20 Hz, 1 H) 7.93 (d, J = 2.54 Hz, 1 H) 63kf ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.35 (t, J = 7.13 Hz, 4 H) 1.74 (br. s., 4 H) 2.04-2.15(m, 1 H) 2.34 (s, 3 H) 2.37 (s, 3 H) 2.44-2.58 (m, 1 H) 3.31 (d, J =2.34 Hz, 2 H) 3.54-3.89 (m, 3 H) 4.34 (dd, J = 7.13, 3.22 Hz, 2 H) 4.61(s, 1 H) 6.10 (s, 1 H) 6.51-6.65 (m, 1 H) 7.03 (d, J = 2.15 Hz, 1 H)7.28 (s, 1 H) 7.42-7.50 (m, 1 H) 7.54 (s, 1 H) 7.76-7.88 (m, 2 H)7.90-8.01 (m, 1 H) 8.33 (s, 1 H) 63kg ¹H NMR (400 MHz, MeOH-d4): δ ppm1.29 (t, J = 7.1 Hz, 3H), 1.55 (s, 3H), 1.58 (d, J = 5.8 Hz, 1H), 1.88(m, 1H), 2.29 (m, 6H), 3.04 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 4.24(m, 2H), 6.68 (q, J = 6.9 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.36 (m,2H), 7.45 (m, 1H), 7.52 (s, 2H), 7.53 (d, J = 2.8 Hz, 1H), 7.63 (dd, J =8.2, 2.0 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H) 63kh ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (td, J = 7.1, 2.1 Hz,3H), 1.50 (s, 3H), 1.53 (d, J = 5.7 Hz, 1H), 1.79 (m, 3H), 2.09 (dd, J =13.1, 8.8 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H),3.50 (s, 3H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H),4.17 (m, 2H), 5.46 (s, 1H), 6.67 (q, J = 6.7 Hz, 1H), 7.12 (t, J = 8.6Hz, 1H), 7.40 (m, 4H), 7.52 (s, 4H), 7.54 (s, 1H), 7.62 (dd, J = 8.2,2.1 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H) 63ki ¹H NMR (400 MHz, MeOH-d4): δppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (dd, J = 11.2, 5.2 Hz, 5H), 1.75 (dd,J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J =11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.49 (m, 2H), 3.51 (s, 3H),3.84 (dd, J = 8.7, 7.3 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.44 (s,1H), 6.66 (q, J = 6.9 Hz, 1H), 7.26 (m, 1H), 7.45 (m, 8H), 7.70 (d, J =7.2 Hz, 1H) 63kj ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz,3H), 1.53 (dd, J = 11.0, 5.2 Hz, 4H), 1.77 (dd, J = 13.2, 7.4 Hz, 1H),2.13 (dd, J = 13.1, 8.8 Hz, 1H), 2.80 (d, J = 11.1 Hz, 1H), 2.93 (d, J =11.1 Hz, 1H), 3.46 (m, 1H), 3.53 (m, 2H), 3.91 (t, J = 8.1 Hz, 1H), 4.19(qd, J = 7.1, 1.4 Hz, 2H), 5.47 (s, 1H), 6.69 (q, J = 6.9 Hz, 1H), 7.35(m, 1H), 7.45 (m, 4H), 7.54 (d, J = 4.6 Hz, 4H), 7.65 (m, 3H), 7.77 (d,J = 8.2 Hz, 1H) 63kk ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1Hz, 3H), 1.51 (m, 4H), 1.74 (dd, J = 13.1, 7.4 Hz, 1H), 2.10 (dd, J =13.1, 8.8 Hz, 1H), 2.29 (d, J = 9.9 Hz, 6H), 2.39 (s, 3H), 2.77 (d, J =11.1 Hz, 1H), 2.90 (d, J = 11.1 Hz, 1H), 3.54 (tq, J = 14.0, 7.9, 6.7Hz, 4H), 3.88 (dd, J = 8.7, 7.4 Hz, 1H), 4.17 (m, 2H), 5.74 (s, 1H),6.41 (d, J = 2.3 Hz, 1H), 6.77 (q, J = 6.6 Hz, 1H), 7.19 (d, J = 7.8 Hz,1H), 7.36 (dd, J = 7.6, 2.1 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.59 (d,J = 1.9 Hz, 1H), 7.72 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H) 63kl ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dd, J = 11.1, 5.8Hz, 5H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz,1H), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H),3.55 (d, J = 5.0 Hz, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (m, 2H),4.65 (s, 2H), 5.78 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.87 (q, J = 6.5Hz, 1H), 7.47 (dd, J = 10.9, 8.2 Hz, 3H), 7.59 (m, 2H), 7.79 (dd, J =8.3, 2.1 Hz, 1H), 7.93 (d, J = 2.3 Hz, 2H) 63km ¹H NMR (400 MHz,MeOH-d4): δ ppm 7.61-7.49 (m, 4H), 7.35-7.27 (m, 2H), 6.77 (dd, J = 8.4,1.8 Hz, 1H), 6.60 (q, J = 7.3 Hz, 1H), 5.55-5.46 (m, 1H), 4.24-4.13 (m,4H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 2.93-2.71 (m, 4H), 2.14-1.94 (m,3H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H), 1.56-1.48 (m, 1H), 1.51 (s, 3H),1.27 (td, J = 7.1, 2.0 Hz, 3H). 63kn ¹H NMR (400 MHz, MeOH-d4): δ ppm8.71 (d, J = 5.2 Hz, 2H), 8.02 (td, J = 7.7, 1.7 Hz, 1H), 7.78-7.68 (m,3H), 7.51 (tt, J = 7.9, 3.3 Hz, 5H), 6.92 (d, J = 6.5 Hz, 1H), 5.81 (d,J = 3.8 Hz, 2H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 3.83 (s, 1H), 3.56 (s,6H), 3.57-3.46 (m, 1H), 2.89 (d, J = 11.0 Hz, 2H), 2.76 (d, J = 11.0 Hz,2H), 2.09 (dd, J = 13.1, 8.9 Hz, 1H), 1.74 (dd, J = 13.1, 7.3 Hz, 1H),1.52 (dd, J = 10.9, 5.5 Hz, 5H), 1.31-1.22 (m, 6H) 63ko ¹H NMR (400 MHz,MeOH-d4): δ ppm 8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, 1H), 7.73 (dd, J =15.2, 7.7 Hz, 2H), 7.60-7.48 (m, 2H), 5.69 (s, 1H), 4.18 (q, J = 7.1 Hz,2H), 3.83 (t, J = 8.1 Hz, 1H), 3.54-3.43 (m, 4H), 2.89 (d, J = 11.1 Hz,1H), 2.75 (d, J = 11.0 Hz, 1H), 2.14-2.04 (m, 1H), 1.74 (dd, J = 13.0,7.4 Hz, 1H), 1.50 (dd, J = 10.6, 5.5 Hz, 5H), 1.26 (t, J = 7.2 Hz, 4H)63kp ¹H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 1H), 7.76 (s, 2H), 7.66(d, J = 16.1 Hz, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.1 Hz,1H), 6.77 (d, J = 7.1 Hz, 1H), 6.41 (s, 1H), 5.74 (d, J = 2.7 Hz, 1H),4.68 (s, 2H), 4.18 (d, J = 7.6 Hz, 2H), 3.84 (t, J = 8.1 Hz, 1H), 3.56(s, 3H), 3.49 (s, 1H), 3.30 (d, J = 3.4 Hz, 9H), 2.89 (d, J = 11.1 Hz,1H), 2.76 (d, J = 11.0 Hz, 1H), 2.37 (d, J = 14.1 Hz, 5H), 1.79-1.69 (m,1H), 1.51 (d, J = 8.8 Hz, 4H), 1.30-1.21 (m, 3H) 63kq ¹H NMR (400 MHz,MeOH-d4): δ ppm 7.98 (s, 1H), 7.76 (d, J = 5.1 Hz, 2H), 7.63 (s, 1H),7.48 (d, J = 13.3 Hz, 3H), 6.77 (d, J = 6.8 Hz, 1H), 6.41 (s, 1H), 5.74(s, 1H), 4.66 (s, 2H), 4.18 (d, J = 7.4 Hz, 2H), 3.82 (t, J = 8.2 Hz,1H), 3.56 (s, 3H), 3.50 (s, 1H), 2.89 (d, J = 11.0 Hz, 1H), 2.75 (d, J =11.1 Hz, 1H), 2.39 (s, 6H), 1.74 (dd, J = 13.0, 7.2 Hz, 1H), 1.51 (s,4H), 1.30-1.22 (m, 3H) 63kr ¹H NMR (400 MHz, MeOH-d4): δ ppm 8.43 (d, J= 2.5 Hz, 1H), 7.98 (d, J = 10.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.71(d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 6.83 (dd, J = 19.6, 7.7 Hz, 2H), 6.42(d, J = 2.3 Hz, 1H), 5.74 (s, 1H), 4.35 (q, J = 7.0 Hz, 2H), 4.17 (q, J= 7.1 Hz, 2H), 3.55 (s, 3H), 3.48 (d, J = 13.0 Hz, 1H), 2.88 (d, J =11.0 Hz, 1H), 2.74 (d, J = 11.0 Hz, 1H), 2.39 (s, 3H), 2.07 (dd, J =13.0, 8.9 Hz, 1H), 1.73 (dd, J = 13.0, 7.2 Hz, 1H), 1.50 (d, J = 8.3 Hz,4H), 1.38 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). 63ks ¹H NMR(400 MHz, MeOH-d4): δ ppm 8.46 (s, 1H), 7.99 (s, 2H), 7.83-7.69 (m, 2H),7.64 (s, 1H), 6.80 (d, J = 5.3 Hz, 1H), 6.42 (s, 1H), 5.74 (s, 1H), 4.18(d, J = 7.3 Hz, 2H), 3.94 (d, J = 2.7 Hz, 3H), 3.86 (t, J = 8.1 Hz, 1H),3.56 (s, 3H), 3.50 (s, 1H), 2.91 (d, J = 11.0 Hz, 1H), 2.77 (d, J = 11.6Hz, 1H), 2.39 (d, J = 2.7 Hz, 3H), 2.10 (t, J = 10.9 Hz, 1H), 1.80-1.70(m, 1H), 1.51 (s, 4H), 1.26 (dd, J = 8.3, 5.7 Hz, 3H). 63kt ¹H NMR (400MHz, MeOH-d4): δ ppm 7.67 (d, J = 8.5 Hz, 1H), 7.44 (ddd, J = 8.0, 4.8,2.6 Hz, 2H), 7.32-7.24 (m, 2H), 7.07 (dd, J = 8.4, 2.5 Hz, 1H), 6.99 (d,J = 7.6 Hz, 1H), 6.76 (q, J = 6.9 Hz, 1H), 5.51 (s, 1H), 4.27 (dd, J =7.0, 2.0 Hz, 1H), 4.25-4.13 (m, 4H), 3.76 (s, 2H), 3.58 (s, 2H), 3.51(d, J = 14.9 Hz, 2H), 3.42 (s, 3H), 3.08 (d, J = 11.4 Hz, 1H), 2.99 (d,J = 11.4 Hz, 1H), 2.28 (dd, J = 13.3, 8.7 Hz, 1H), 1.88 (dd, J = 13.3,8.0 Hz, 1H), 1.57 (p, J = 5.4 Hz, 4H), 1.29 (t, J = 7.1 Hz, 3H) 63ku ¹HNMR (400 MHz, MeOH-d4): δ ppm 8.97 (d, J = 1.5 Hz, 1H), 8.80 (dd, J =2.6, 1.5 Hz, 1H), 8.71 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H),7.64-7.55 (m, 1H), 6.87 (q, J = 6.7 Hz, 1H), 5.62 (s, 1H), 4.23-4.13 (m,2H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 3.60-3.42 (m, 3H), 2.89 (d, J =11.0 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz,1H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 1.51 (dt, J = 10.9, 5.6 Hz, 3H),1.26 (t, J = 7.1 Hz, 2H)

Example 64a: (S)-Octyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

To a flask equipped with a Dean Stark trap were added(2S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2-carboxylicacid (1 g, 1.78 mmol), toluene (25 mL), and p-toluene sulfonic acidmonohydrate (336 mg, 1.77 mmol), and n-octanol (690 mg, 5.30 mmol). Thereaction mixture was heated to reflux for 48 h, cooled to RT, andconcentrated in vacuo. Purification on a 120 g Isco RediSep silicacartridge (CH₂Cl₂/MeOH/NH₄OH) provided the title compound as a whitesolid.

Applying the generic scheme below, the following examples of Table 19awere prepared as described above for (S)-octyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 64a), using the appropriate alcohol.

TABLE 19a

Ex. LCMS No. R CAS Name (MH+) 64a

(S)-Octyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 679.2 64b

(S)-cyclopentyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate635.1 64c

(S)-pentyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 637 64d

(S)-cyclohexyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylate648 64e

(S)-propyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 608 64f

(S)-neopentyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 636 64g

(S)-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 622 64h

(S)-isopropyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 622

TABLE 19b NMR Data for Compounds of Table 19a Ex. No. NMR 64a ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.82-0.96 (m, 3 H), 1.20-1.47 (m, 10 H),1.53-1.79 (m, 6 H), 2.04 (dd, J = 13.6, 8.8 Hz, 1 H), 2.38 (s, 3 H),2.49 (dd, J = 13.6, 8.8 Hz, 1 H), 3.28 (s, 2 H), 3.42-3.85 (m, 4 H),4.16-4.39 (m, 2 H), 4.60 (t, J = 8.8 Hz, 1 H), 5.81 (s, 1 H), 6.42 (d, J= 2.2 Hz, 1 H), 6.85 (q, J = 6.6 Hz, 1 H), 7.46-7.60 (m, 2 H), 7.71 (d,J = 8.3 Hz, 1 H), 7.93 (d, J = 2.4 Hz, 1 H) 64b ¹H NMR (400 MHz,MeOH-d4): δ ppm 1.50-2.10 (m, 13 H), 2.38 (s, 3 H), 2.45 (dd, J = 13.6,8.8 Hz, 1 H), 3.27 (d, J = 1.2 Hz, 2 H), 3.43-3.76 (m, 4 H), 4.55 (t, J= 8.7 Hz, 1 H), 5.26-5.39 (m, 1 H), 5.74 (s, 1 H), 6.42 (d, J = 2.3 Hz,1 H), 6.83 (q, J = 6.6 Hz, 1 H), 7.45-7.59 (m, 2 H), 7.71 (d, J = 8.4Hz, 1 H), 7.93 (d, J = 2.3 Hz, 1 H) 64c ¹H NMR (400 MHz, MeOH-d4): δ ppm0.94 (t, J = 7.2 Hz, 3H), 1.35-1.39 (m, 4H), 1.52-1.56 (m, 4 H),1.64-1.71 (m, 2H), 1.74-1.79 (m, 1H), 2.08-2.14 (m, 1H), 2.40 (s, 3 H),2.77 (d, J = 10.8 Hz, 1H), 2.92 (d, J = 10.8 Hz, 1H), 3.48-3.58 (m, 4H), 3.83-3.87 (m, 1H), 4.13-4.18 (m, 2H), 5.69 (s, 1 H), 6.43 (d, J =2.0 Hz, 1H), 6.81-6.86 (m, 1H), 7.51-7.55 (m, 2H), 7.72 (d, J = 8.4 Hz,1H), 7.95 (d, J = 2.0 Hz, 1H) 64d ¹H NMR (400 MHz, MeOH-d4): δ ppm1.31-1.56 (m, 10H), 1.75-1.80 (m, 3H), 1.85-1.89 (m, 2H), 2.08-2.13 (m,1H), 2.39 (s, 3H), 2.76 (d, J = 10.8 Hz, 1 H), 2.93 (d, J = 10.8 Hz,1H), 3.50-3.58 (m, 4H), 3.81-3.84 (m, 1H), 4.77-4.83 (m, 1H), 5.69 (s, 1H), 6.42 (d, J = 2.0 Hz, 1H), 6.81-6.86 (m, 1H), 7.51-7.55 (m, 2H), 7.72(d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H) 64e ¹H NMR (400 MHz,MeOH-d4): δ ppm 0.98 (t, J = 7.6 Hz, 3H), 1.54-1.59 (m, 4 H), 1.66 (m,2H), 1.81-1.86 (m, 1H), 2.17-2.23 (m, 1H), 2.40 (s, 3H), 2.89 (d, J =11.2 Hz, 1H), 3.00 (d, J = 11.2 Hz, 1H), 3.47-3.62 (m, 4H), 4.03 (t, J =8.0 Hz, 1H), 4.11-4.18 (m, 2H), 5.70 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H),6.84 (q, 1H), 7.51-7.55 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.95 (d, J =2.4 Hz, 1H) 64f ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.98 (s, 9H), 1.50-1.58(m, 4 H), 1.77-1.82 (m, 1H), 2.12-2.17 (m, 1H), 2.40 (s, 3H), 2.79 (d, J= 11.2 Hz, 1H), 2.94 (d, J = 11.2 Hz, 1H), 3.52-3.58 (m, 4H), 3.83-3.93(m, 3H), 5.70 (s, 1 H), 6.43 (d, J = 2.4 Hz, 1H), 6.81-6.86 (m, 1H),7.52-7.55 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H)64g ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.95 (t, J = 7.6 Hz, 3H), 1.37-1.43(m, 2H), 1.50-1.54 (m, 4H), 1.60-1.67 (m, 2H), 1.72-1.77 (m, 1H),2.06-2.12 (m, 1H), 2.38 (s, 3 H), 2.75 (d, J = 11.2 Hz, 1 H), 2.90 (d, J= 11.2 Hz, 1H), 3.45-3.58 (m, 4 H), 3.83-3.86 (m, 1H), 4.10-4.20 (m,2H), 5.67 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.80-6.85 (m, 1 H),7.50-7.53 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H)64h ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.85 (d, J = 6.8 Hz, 6H), 1.42-1.47(m, 4H), 1.68-1.73 (m, 1H), 1.82-1.89 (m, 1H), 2.05-2.10 (m, 1H), 2.28(s, 3H), 2.74 (d, J = 11.2 Hz, 1 H), 2.87 (d, J = 11.2 Hz, 1H),3.37-3.48 (m, 4H), 3.81-3.91 (m, 3H), 5.58 (s, 1H), 6.30 (d, J = 2.0 Hz,1H), 6.70-6.75 (m, 1 H), 7.40-7.43 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H),7.83 (d, J = 2.4 Hz, 1H)

Example 65a: (S)-Tert-butyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

Step 1:

To a mixture of(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (2.8 g, 4.1 mmol) in t-BuOH (50 mL) were added BOC₂O (3.5 g, 16.5mmol) and DMAP (0.201 g, 1.65 mmol), and the reaction was heated to 50°C. for 45 min. Then the reaction was cooled to RT and concentrated invacuo. Purification on a 220 g Isco RediSep silica cartridge(EtOAc/heptane) provided (S)-2-benzyl 3-tert-butyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2, 8-diazaspiro[4.5]decane-2,3-dicarboxylate as anoff-white solid.

Step 2:

To a solution of (S)-2-benzyl 3-tert-butyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(1.35 g, 1.7 mmol) in EtOAc (130 mL) was added 5% (w/w) Pd/C (130 mg).The solution was degassed, charged with 1 atm H₂ (balloon), and stirredat RT for 3.5 h. Then the solids were filtered through celite, washedwith EtOAc/methanol, and the filtrate was concentrated in vacuo.Purification on a 220 g Isco RediSep silica cartridge(CH₂Cl₂/MeOH/NH₄OH) provided the title compound as an off-white solid.

Applying the generic scheme below, the following examples of Table 20awere prepared as described above for (S)-tert-butyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 65).

TABLE 20a

Ex. LCMS No. Ar CAS Name (MH+) 65a

(S)-tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate623 65b

(S)-tert-butyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4- propylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 630 65c

(S)-tert-butyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 693 65d

(S)-tert-butyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 722

TABLE 20b NMR Data for Compounds of Table 20a Ex. No. NMR 65a ¹H NMR(400 MHz, MeOH-d4): δ ppm 1.54 (s, 9 H), 1.57-1.72 (m, 4 H), 2.02 (dd, J= 13.62, 8.44 Hz, 1 H), 2.38 (s, 3 H), 2.40-2.47 (m, 1 H), 3.18-3.37 (m,2 H), 3.47-3.75 (m, 4 H), 4.49 (t, J = 8.61 Hz, 1 H), 5.76 (s, 1 H),6.42 (d, J = 2.34 Hz, 1 H), 6.84 (q, J = 6.57 Hz, 1 H), 7.46-7.59 (m, 2H), 7.71 (d, J = 8.35 Hz, 1 H), 7.93 (d, J = 2.39 Hz, 1 H) 65b ¹H NMR(400 MHz, MeOH-d4): δ ppm 0.96 (t, J = 7.35 Hz, 3 H) 1.53 (s, 9 H)1.56-1.77 (m, 6 H) 1.99 (dd, J = 13.52, 8.25 Hz, 1 H) 2.37-2.42 (m, 4 H)2.59-2.73 (m, 2 H) 3.14-3.29 (m, 2 H) 3.45-3.74 (m, 4 H) 4.43 (t, J =8.47 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J = 2.29 Hz, 1 H) 6.72 (q, J = 6.74Hz, 1 H) 7.23 (d, J = 1.61 Hz, 1 H) 7.33 (dd, J = 8.10, 1.61 Hz, 1 H)7.63 (d, J = 8.10 Hz, 1 H) 7.85 (d, J = 2.34 Hz, 1 H) 65c ¹H NMR (400MHz, MeOH-d4): δ ppm .49 (s, 4 H) 1.50 (s, 5 H) 1.53-1.64 (m, 4 H)1.90-2.01 (m, 1 H) 2.27 (s, 3 H) 2.30 (s, 3 H) 2.31-2.37 (m, 1 H) 2.38(s, 3 H) 3.09-3.25 (m, 2 H) 3.43-3.70 (m, 4 H) 4.32-4.42 (m, 1 H) 5.74(s, 1 H) 6.39 (d, J = 2.29 Hz, 1 H) 6.75 (q, J = 6.67 Hz, 1 H) 7.19 (d,J = 7.91 Hz, 1 H) 7.36 (dd, J = 7.81, 1.81 Hz, 1 H) 7.42 (s, 1 H) 7.58(s, 1 H) 7.68-7.78 (m, 2 H) 7.93 (d, J = 2.29 Hz, 1 H) 65d ¹H NMR (400MHz, MeOH-d4): δ ppm 1.31 (d, J = 6.05 Hz, 6 H) 1.50 (s, 4 H) 1.51 (s, 5H) 1.55-1.70 (m, 4 H) 1.92-2.06 (m, 1 H) 2.38 (s, 3 H) 2.39-2.48 (m, 1H) 3.16-3.27 (m, 2 H) 3.47-3.75 (m, 4 H) 4.46 (t, J = 8.64 Hz, 1 H) 4.63(dt, J = 12.10, 6.05 Hz, 1 H) 5.85 (s, 1 H) 6.39 (d, J = 2.29 Hz, 1 H)6.76 (q, J = 6.62 Hz, 1 H) 6.97 (d, J = 8.79 Hz, 2 H) 7.55-7.63 (m, 3 H)7.67-7.77 (m, 2 H) 7.93 (d, J = 2.29 Hz, 1 H)

Example 66a: (S)-2-(Dimethylamino)ethyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

Step 1:

To a mixture of(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (85 mg, 0.16 mmol) in THF (10 mL) was added BOC₂O (4 g, 18.6 mmol)in THF (10 mL), and the reaction mixture was stirred at RT for 16 h.Then the reaction was diluted with CH₂Cl₂, cooled to 0° C., and the pHadjusted to 2 with 2 N HCl. The reaction mixture was then extractedCH₂Cl₂ and concentrated in vacuo to provide(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid as an off-white solid that was used directly without furtherpurification.

Step 2:

To a solution of(S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (1.6 g, 2.45 mmol) in DMF (24 mL) wereadded (2-chloro-ethyl)-dimethyl-amine hydrochloride (535 mg, 3.7 mmol)and K₂CO₃ (1.0 g, 7.4 mmol), and the reaction mixture was heated at 65°C. for 16 h. Then the reaction was cooled to RT, partitioned betweenEtOAc and water, and extracted. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification via prep-HPLC column chromatography (CH₂Cl₂/MeOH/NH₄OH)provided (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl)8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylateas an off-white solid.

Step 3:

To a solution of (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl)8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate(1.4 g, 1.86 mmol) in CH₂Cl₂ (9 mL) was added TFA (4.5 mL), and thereaction was stirred at RT for 2 h. Then the reaction was concentratedin vacuo and the residue was partitioned between CH₂Cl₂ and aqueousNaHCO₃, and extracted. The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. Purification viaprep-HPLC column chromatography (CH₂Cl₂/EtOH/NH₄OH) provided the titlecompound as an off-white solid.

Applying the generic scheme below, the following examples of Table 21awere prepared as described above for (S)-2-(dimethylamino)ethyl8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 66a), using the appropriate alkylating agent.

TABLE 21a

Ex. LCMS No. R^(X) R^(Y) R^(Z) CAS Name (MH+) 66a H

H (S)-2-(dimethylamino)ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate638 66b H

(S)-2-(dimethylamino)-2-oxoethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl- 1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate652 66c H

H (S)-2-(((R)-2-amino-3- methylbutanoyl)oxy)ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate710 66d H

H (S)-2-(pivaloyloxy)ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- 1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate695

TABLE 21b NMR Data for Compounds of Table 21a Ex. No. NMR 66a ¹H NMR(400 MHz, DMSO-d6): δ ppm 1.59 (d, J = 5.08 Hz, 4 H) 2.00 (dd, J =13.15, 9.84 Hz, 1 H) 2.22-2.38 (m, 4 H) 2.77 (d, J = 3.37 Hz, 6 H) 3.14(br. s., 2 H) 3.41 (br. s., 2 H) 3.60 (br. s., 2 H) 4.45 (dd, J = 5.71,3.90 Hz, 1 H) 4.49-4.68 (m, 2 H) 5.90 (br. s., 1 H) 6.39 (d, J = 2.39Hz, 1 H) 7.15 (d, J = 5.86 Hz, 1 H) 7.53-7.73 (m, 3 H) 8.14 (d, J = 2.39Hz, 1 H) 9.65 (br. s., 1 H) 10.59 (br. s., 1 H), 10.80 (br. s., 1 H).66b ¹H NMR (400 MHz, DMSO-d6): δ ppm 1.46-1.77 (m, 4 H) 2.11 (dd, J =13.42, 8.40 Hz, 1 H) 2.31 (s, 3 H) 2.38 (dd, J = 13.42, 9.08 Hz, 1 H)2.78-2.88 (m, 3 H) 2.89-2.98 (m, 3 H) 3.16 (br. s., 2 H) 3.59-3.77 (m, 3H) 4.65 (t, J = 6.17 Hz, 1 H) 4.83-4.97 (m, 1 H) 5.00-5.12 (m, 1 H) 6.03(br. s., 1 H) 6.42 (d, J = 2.29 Hz, 1 H) 7.20 (d, J = 5.47 Hz, 1 H)7.57-7.76 (m, 3 H) 8.17 (d, J = 2.34 Hz, 1 H) 9.22 (d, J = 4.44 Hz, 1 H)10.63 (br. s., 1 H). 66c ¹H NMR (400 MHz, DMSO-d6): δ ppm 0.98 (dd, J =15.52, 6.93 Hz, 6 H) 1.46-1.70 (m, 4 H) 1.94 (dd, J = 13.15, 9.64 Hz, 1H) 2.20 (td, J = 6.91, 4.88 Hz, 1 H) 2.26-2.38 (m, 4 H) 3.14 (br. s., 2H) 3.51 (br. s., 2 H) 3.58-3.70 (m, 3 H) 3.88 (br. s., 1 H) 4.29-4.49(m, 4 H) 4.55 (br. s., 1 H) 5.84 (br. s., 1 H) 6.42 (d, J = 2.34 Hz, 1H) 7.16 (d, J = 5.66 Hz, 1 H) 7.50-7.76 (m, 3 H) 8.17 (d, J = 2.34 Hz, 1H) 8.66 (br. s., 3 H) 9.47 (br. s., 1 H) 10.52-10.84 (m, 1 H). 66d ¹HNMR (400 MHz, DMSO-d6): δ ppm 1.11-1.18 (m, 9 H) 1.48 (s, 3 H) 1.54-1.72(m, 4 H) 1.74-2.01 (m, 1 H) 2.22-2.43 (m, 4 H) 3.15 (d, J = 3.56 Hz, 2H) 3.58-3.80 (m, 4 H) 4.60 (d, J = 5.71 Hz, 1 H) 6.06 (br. s., 1 H) 6.42(s, 1 H) 6.74-6.88 (m, 1 H) 7.22 (d, J = 5.47 Hz, 1 H) 7.57-7.76 (m, 4H) 8.18 (s, 1 H) 9.19-9.56 (m, 1 H) 10.74 (br. s., 1 H).

Example 67a: (S)-isopropyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

To a solution of the compound of Example 1m (400 mg, 0.53 mmol) inpropan-2-ol (5 mL) was added thionyl chloride (2 drops) at 0° C. Themixture was warmed to RT and then heated to reflux for 2 h. Then thereaction mixture was cooled to RT, concentrated and neutralized withsaturated aqueous NaHCO₃ solution to pH 7-8. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, concentrated in vacuo and purifiedby flash column (0-10% MeOH in DCM) on silica gel to afford the titlecompound as a white solid.

¹H NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J=2.3 Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 7.70 (dd, J=8.2, 1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.43 (s,1H), 7.37 (d, J=7.8 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.76 (q, J=6.8 Hz,1H), 6.41 (d, J=2.3 Hz, 1H), 5.74 (s, 1H), 5.01 (m, 1H), 3.76 (dd,J=8.7, 7.0 Hz, 1H), 3.61-3.42 (m, 4H), 2.88 (d, J=11.1 Hz, 1H), 2.72 (d,J=11.0 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.05 (dd,J=13.1, 8.9 Hz, 1H), 1.71 (dd, J=13.0, 7.0 Hz, 1H), 1.50 (m, 4H), 1.24(dd, J=6.2, 3.9 Hz, 6H). LCMS (MH⁺): 679.

Applying the generic scheme below, the following examples of Table 22were prepared as described above for (S)-isopropyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 67a), using the appropriate alcohol.

TABLE 22a Ex. LCMS No. R¹ CAS Name (MH+) 67b

(S)-cyclopentyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylate705 67c CH₃ (S)-methyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3- 650methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylate67d

(S)-propyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylate679

TABLE 22b NMR Data for Compounds of Table 22 Ex. No. NMR 67b ¹H NMR (400MHz, MeOH-d4): δ ppm 7.96 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H),7.71 (dd, J = 8.2, 1.8 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.44 (s, 1H),7.37 (dd, J = 7.9, 1.9 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.76 (q, J =6.9 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 5.74 (s, 1H), 5.21-5.14 (m, 1H),3.76 (dd, J = 8.8, 6.9 Hz, 1H), 3.61-3.42 (m, 4H), 2.88 (d, J = 11.0 Hz,1H), 2.72 (d, J = 11.0 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.28 (s,3H), 2.04 (dd, J = 13.1, 8.8 Hz, 1H), 1.87 (d, J = 7.3 Hz, 2H),1.77-1.56 (m, 7H), 1.50-1.45 (m, 4H) 67c ¹H NMR (400 MHz, MeOH-d4): δppm 7.96 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.71 (dd, J =8.2, 1.6 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.44 (s, 1H), 7.37 (dd, J =7.8, 1.6 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.76 (q, J = 6.5 Hz, 1H),6.41 (d, J = 2.3 Hz, 1H), 5.74 (s, 1H), 3.83 (t, J = 8.0 Hz, 1H), 3.71(s, 3H), 3.61-3.41 (m, 4H), 2.86 (d, J = 11.0 Hz, 1H), 2.74 (d, J = 11.0Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 2.06 (dd, J = 13.0,8.7 Hz, 1H), 1.72 (dd, J = 13.0, 7.2 Hz, 1H), 1.55-1.43 (m, 4H) 67d ¹HNMR (400 MHz, MeOH-d4): δ ppm 0.95 (m, 3H), 1.49 (dt, J = 12.0, 6.0 Hz,4H), 1.69 (m, 3H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.29 (d, J = 10.3Hz, 6H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz,1H), 3.30 (m, 4H), 3.51 (dt, J = 27.9, 6.6 Hz, 4H), 3.81 (dd, J = 8.7,7.1 Hz, 1H), 4.08 (m, 2H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.76(q, J = 6.7 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.40 (m, 2H), 7.59 (d, J= 1.8 Hz, 1H), 7.72 (m, 2H), 7.96 (d, J = 2.4 Hz, 1H)

Example 68a: (S)-isopropyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

The title compound was prepared as described for (S)-isopropyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 67a) starting with(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 11). Applying the generic scheme below, the followingexamples of Table 23 were prepared as described above for (S)-isopropyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 68a), using the appropriate alcohol.

TABLE 23a Ex. LCMS No. R¹ CAS Name (MH+) 68a

(S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-ypethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 709 68b

(S)-cyclopentyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 735 68c

(S)-propyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 709

TABLE 23b NMR Data for Compounds of Table 23 Ex. No. NMR 68a ¹H NMR (400MHz, MeOH-d4): δ ppm 1.26 (m, 14H), 1.49 (dt, J = 10.9, 5.2 Hz, 4H),1.72 (dd, J = 13.1, 7.0 Hz, 1H), 2.05 (dd, J = 13.1, 8.8 Hz, 1H), 2.39(s, 3H), 2.72 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (m,4H), 3.77 (dd, J = 8.8, 7.0 Hz, 1H), 4.63 (hept, J = 6.0 Hz, 1H), 5.01(p, J = 6.2 Hz, 1H), 5.74 (s, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.76 (q, J= 6.6 Hz, 1H), 6.96 (m, 2H), 7.57 (m, 3H), 7.70 (m, 2H), 7.95 (d, J =2.3 Hz, 1H) 68b ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (d, J = 6.0 Hz,8H), 1.50 (m, 4H), 1.67 (ddd, J = 33.0, 12.8, 5.6 Hz, 8H), 1.88 (m, 3H),2.05 (dd, J = 13.1, 8.9 Hz, 1H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz,1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (dt, J = 21.1, 6.5 Hz, 4H), 3.78(dd, J = 8.8, 7.0 Hz, 1H), 4.64 (p, J = 6.0 Hz, 1H), 5.18 (td, J = 5.9,2.7 Hz, 1H), 5.75 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.6Hz, 1H), 6.97 (m, 2H), 7.59 (m, 3H), 7.71 (m, 2H), 7.95 (d, J = 2.4 Hz,1H) 68c ¹H NMR (400 MHz, MeOH-d4): δ ppm 0.94 (t, J = 7.4 Hz, 3H), 1.32(d, J = 6.0 Hz, 6H), 1.50 (dt, J = 12.3, 6.0 Hz, 4H), 1.69 (m, 3H), 2.07(dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.73 (d, J = 11.0 Hz, 1H),2.88 (d, J = 11.0 Hz, 1H), 3.52 (dp, J = 20.9, 7.5 Hz, 4H), 3.81 (dd, J= 8.7, 7.1 Hz, 1H), 4.09 (m, 2H), 4.64 (h, J = 6.0 Hz, 1H), 5.74 (s,1H), 6.40 (d, J = 2.4 Hz, 1H), 6.76 (q, J = 6.7 Hz, 1H), 6.96 (m, 2H),7.58 (m, 3H), 7.71 (m, 2H), 7.95 (d, J = 2.4 Hz, 1H)

Example 69a: (S)-isopropyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

The title compound was prepared as described for (S)-isopropyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 67a) starting with(S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34c).

Applying the generic scheme below, the following examples of Table 24were prepared as described above for (S)-isopropyl8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 68a), using the appropriate alcohol.

TABLE 24a Ex. LCMS No. R¹ CAS Name (MH+) 69a

(S)-isopropyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 605 69b

(S)-cyclopentyl 8-(2-amino-6-((R)-1-(4′-chloro-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate735 69c

(S)-propyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 605 69d

(S)-tetrahydro-2H-pyran-4-yl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate 645

TABLE 24b NMR Data for Compounds of Table 24 Ex. No. NMR 69a ¹H NMR (400MHz, MeOH-d4): δ ppm 1.25 (dd, J = 6.3, 3.2 Hz, 6H), 1.52 (m, 4H), 1.74(dd, J = 13.1, 7.1 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.75 (d, J= 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, 1H), 3.49 (m, 4H), 3.80 (dd, J =8.8, 7.1 Hz, 1H), 5.02 (hept, J = 6.2 Hz, 1H), 5.47 (d, J = 7.8 Hz, 1H),6.63 (q, J = 6.8 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.48 (m, 6H), 7.67(d, J = 8.5 Hz, 1H) 69b ¹H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (d, J =6.0 Hz, 8H), 1.50 (m, 4H), 1.67 (ddd, J = 33.0, 12.8, 5.6 Hz, 8H), 1.88(m, 3H), 2.05 (dd, J = 13.1, 8.9 Hz, 1H), 2.39 (s, 3H), 2.73 (d, J =11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (dt, J = 21.1, 6.5 Hz,4H), 3.78 (dd, J = 8.8, 7.0 Hz, 1H), 4.64 (q, J = 6.0 Hz, 1H), 5.18 (td,J = 5.9, 2.7 Hz, 1H), 5.75 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.75 (q, J= 6.6 Hz, 1H), 6.97 (m, 2H), 7.59 (m, 3H), 7.71 (m, 2H), 7.95 (d, J =2.4 Hz, 1H) 69c ¹H NMR (MeOH-d4): δ ppm 0.95 (t, J = 7.4 Hz, 3H), 1.52(dt, J = 14.2, 4.9 Hz, 4H), 1.71 (ddd, J = 31.8, 13.7, 7.1 Hz, 3H), 2.10(dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0Hz, 1H), 3.50 (ddd, J = 19.5, 7.9, 4.8 Hz, 4H), 3.84 (dd, J = 8.7, 7.2Hz, 1H), 4.10 (m, 2H), 4.88 (s, 8H), 5.48 (d, J = 7.9 Hz, 1H), 6.63 (q,J = 6.9 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.47 (m, 6H), 7.67 (d, J =8.6 Hz, 1H) 69d ¹H NMR (MeOH-d4): δ ppm 1.61 (m, 6H), 1.82 (dd, J =13.2, 7.5 Hz, 1H), 1.93 (dd, J = 11.6, 6.1 Hz, 2H), 2.03 (s, 1H), 2.20(dd, J = 13.2, 8.8 Hz, 1H), 2.89 (d, J = 11.2 Hz, 1H), 2.99 (d, J = 11.2Hz, 1H), 3.54 (m, 6H), 3.89 (dq, J = 12.1, 3.9 Hz, 2H), 4.04 (dd, J =8.7, 7.5 Hz, 1H), 5.01 (tt, J = 8.3, 4.0 Hz, 1H), 5.48 (s, 1H), 6.64 (q,J = 6.9 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.47 (m, 6H), 7.67 (d, J =8.5 Hz, 1H)

Example 70: (S)-methyl8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

The title compound was prepared as described for (S)-isopropyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 67a) starting with(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34w).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.51 (q, J=7.1, 6.7 Hz, 6H), 1.72 (dd,J=13.0, 7.3 Hz, 1H), 2.07 (dd, J=13.2, 8.7 Hz, 1H), 2.75 (d, J=11.0 Hz,1H), 2.87 (d, J=11.0 Hz, 1H), 3.21 (s, 4H), 3.50 (tdt, J=20.3, 13.5, 7.0Hz, 4H), 3.71 (s, 2H), 3.84 (t, J=8.0 Hz, 1H), 4.87 (m, 1H), 5.57 (s,1H), 6.57 (q, J=6.6 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.41 (s, 2H), 7.48(dd, J=8.5, 2.2 Hz, 1H), 7.75 (m, 3H), 8.07 (d, J=7.8 Hz, 1H), 8.43 (s,1H). LCMS (MH+): 655.

Example 71: (S)-methyl8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

The title compound was prepared as described for (S)-isopropyl8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate(Example 67a) starting with(S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylicacid (Example 34u).

¹H NMR (400 MHz, MeOH-d4): δ ppm 1.54 (dt, J=8.9, 6.0 Hz, 5H), 1.75 (dd,J=13.1, 7.4 Hz, 1H), 2.10 (dd, J=13.1, 8.7 Hz, 1H), 2.77 (d, J=11.0 Hz,1H), 2.89 (d, J=11.0 Hz, 1H), 3.53 (qt, J=14.0, 7.8 Hz, 4H), 3.72 (s,3H), 3.86 (dd, J=8.7, 7.3 Hz, 1H), 4.91 (s, 13H), 5.57 (s, 1H), 6.60 (q,J=6.5 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.49 (dd, J=8.5, 2.3 Hz, 1H),7.60 (d, J=7.7 Hz, 1H), 7.71 (m, 2H), 8.02 (ddd, J=7.9, 1.9, 1.1 Hz,1H), 8.33 (s, 1H). LCMS (MH+): 656. LCMS (MH+): 656.

Example A: In Vitro Inhibition Assays TPH1 and TPH2 Assays

Recombinant human TPH1 (rTPH1 GenBank™ accession no. NP_004179) wasexpressed by cloning full length human TPH1 cDNA in to a bacterialpMAL-c5E expression vector to produce maltose-binding protein (MBP) TPH1fusion proteins. E. coli BL21 (DE3) containing pMAL-c5E-TPH1 was usedfor protein generation and the recombinant protein was purifiedutilizing standard column chromatography techniques. The MBP tagged TPH1(MBP-TPH1) was used directly to screen compounds as described below.Recombinant human TPH2 (rTPH2 GenBank™ accession no. 173353), PheOH(rPheOH GenBank™ accession no. K03020) and TH (rTH GenBank™ accessionno. L20679) with an MBP tag were produced similarly.

TPH1 activities were measured in an assay containing 200 mM ammoniumsulfate, 7 mM DTT, 50 μg/mL catalase, 25 μM ammonium iron sulfate, 50 mMMES, pH 7.1. Test compounds were diluted in 100% DMSO and added to theassay plate in 1 μL aliquots at 100× final concentration. Fiftymicroliters of assay buffer containing 30 nM TPH1 enzyme (MBP tagged)were added to the plate wells containing the test compound by the use ofan Eppendorf repeater pipette. The reaction was initiated by theaddition of 50 μL of assay buffer containing 60 μM tryptophan and 72 μM6-6-methyltetra-hydropterin (2× final concentration) by the use of aMultidrop (LabSystems). Final reaction conditions were 15 nM TPH1enzyme, 30 μM tryptophan, 36 μM 6-methyltetra-hydropterin, 200 mMammonium sulfate, 7 mM DTT, 25 lag/mL catalase, 25 μM ferrous ammoniumsulfate, 50 mM MES, pH 7.1, with atmospheric oxygen at room temperature.The plate was immediately placed onto an M5 plate reader (MolecularDevices) for kinetic fluorescence measurement using an excitationsetting of 300 nm and an emission setting of 335 nm. Fluorescence readsare recorded in kinetic mode for 300 seconds (5 minutes).

Kinetic assay data for compounds at specific concentrations wastranslated into slopes using the Softmax Pro software on a Spectramaxreader, and compound inhibition slopes were compared with wellscontaining enzyme, substrate and cofactor in the absence of inhibitor(100%), and wells containing substrate and cofactor in the absence ofenzyme (0%). DMSO concentration in the assay was 1%. Typically, in theabsence of enzyme, reaction slopes were ˜0. IC₅₀'s were determined usingGraphpad Prism.

Compounds having an IC₅₀ of 10,000 nM or less were considered active.

Inhibition of TPH2 activity by the compounds of the invention wasmeasured similarly. In some instances, compounds of the invention showeddual inhibition of both TPH1 and TPH2.

Data related to TPH1 inhibition activity of the compounds of theinvention is provided below in Table 25. Compounds that inhibit TPH1with an IC₅₀ from 3,000 nM to 10,000 nM are indicated by +. Compoundsthat inhibit TPH1 with an IC₅₀ of less than 3,000 nM but more than 300nM are indicated by ++. Compounds that inhibit TPH1 from 50 nM to 300 nMare indicated by +++. Compounds that inhibit TPH1 with an IC₅₀ less than50 nM are indicated by ++++. Ester prodrugs listed, for example, inTables 18a, 19a, 20a, and 21a-24a, as well as in Examples 70 and 71, arenot expected to be active in this in vitro assay.

TABLE 25 TPH1 Inhibition Data TPH1 Ex. No. Range  1a ++++  1b ++++  1c++++  1d ++++  1e ++++  1f +++  1g ++++  1h ++++  1i +++  1j +++  1k++++  1l ++++  1m ++++  1n ++++  1o ++++  1p ++++  1q ++++  1r ++++  1s++++  1u ++++  1v ++++  1w ++++  1x ++++  1y ++++  1z ++++  1aa ++++ 1ab ++++  1ac ++++  1ad ++++  1ae ++++  1af ++++  1ag ++++  1ah ++++ 1ai ++++  1aj ++++  1ak +++  1al ++++  1am ++++  1an ++++  1ao ++++ 1ap ++++  1aq +++  1ar +++  1as ++++  1at ++++  1au +++  1av ++++  1aw+++  1ax ++++  1ay +++  1az +++  1ba ++++  1bb ++++  1bc ++++  1bd ++++ 1be +++  1bf +++  1bg ++++  1bh ++++  1bi ++++  1bj +++  1bk ++++  1bl++++  1bm ++++  1bn ++++  1bo +++  1bp ++++  1bq ++++  1bv ++++  1bw +++ 1bx ++++  1by ++++  1bz ++++  1ca ++++  1cb ++++  1cc ++++  1cd ++++ 1ce ++++  1cf +++  1cg ++++  1ch +++  1ci ++++  1cj ++++  1ck ++++  1cl++++  1cm ++++  1cn ++++  1co ++++  1cp ++++  1cq ++++  1cr ++++  1cs++++ 10j +++ 10k +++ 10l +++ 10m ++++ 10n ++++ 10o ++++ 10p +++ 10q ++++10r ++++ 10pa +++ 11 +++ 12a +++ 12b ++++ 12c ++++ 13 +++ 14 ++++ 15 +++16 ++ 17 ++++ 18a +++ 18b ++++ 18c ++++ 18d ++++ 18e ++++ 18f ++++ 19a++++ 19b ++++ 19c ++++ 19d +++ 19e ++++ 19f ++++ 19g ++++ 19h ++++ 19i++++ 19j ++++ 19k ++++ 19l ++++ 19m ++++ 19n ++++ 19o ++++ 19p ++++ 19q++++ 19r ++++ 20 ++++ 21 ++++ 22a ++++ 22b ++++ 22c ++++ 23 ++++ 24 +++25 ++++ 26 + 27 +++ 28 +++ 29a ++++ 29b ++++ 29c +++ 29d ++++ 29e +++29f ++++ 29g ++++ 29h ++++ 29i ++++ 29j ++++ 29k +++ 29l ++++ 29m +++29n +++ 29o ++++ 29p ++++ 29q ++++ 29r ++++ 29s ++++ 29t +++ 29u +++ 33+++ 34a ++++ 34b ++++ 34c +++ 34d +++ 34e +++ 34f +++ 34g +++ 34h ++ 34i+++ 34j +++ 34k +++ 34l +++ 34m +++ 34n +++ 34o +++ 34p +++ 34q ++++ 34r+++ 34s +++ 34t +++ 34u ++++ 34v ++++ 34w ++++ 34x ++++ 34y ++++ 34z++++ 34aa ++++ 34ab ++ 34ac ++++ 34ad ++ 34ae ++ 34af ++++ 34ag ++++34ah ++++ 34ai +++ 34aj +++ 34ak +++ 34al + 34am +++ 34an ++++ 34ao ++++34ap +++ 34aq ++++ 34ar ++++ 34as ++++ 34at +++ 34au ++++ 34av ++++ 34aw++++ 34ax +++ 34ay +++ 34az ++ 34ba ++++ 34bb +++ 34bc +++ 34bd ++++34be ++++ 34bf +++ 34bg +++ 34bh ++ 34bi ++++ 34bj ++++ 34bk +++ 34bl+++ 34bm +++ 34bn +++ 34bo +++ 34bp ++++ 34bq +++ 34bu +++ 34bv +++ 34bw+++ 34bx +++ 34by +++ 34ca +++ 34cb +++ 34cc +++ 34cd +++ 34ce +++ 34cf++ 34cg +++ 34ch ++++ 34ci +++ 34cj +++ 34ck +++ 34cl +++ 34cm +++ 34cn+++ 34co +++ 34cp +++ 34cq ++++ 34cr +++ 34cs +++ 34ct ++++ 34cu ++++34cv ++++ 35 +++ 36 + 36b +++ 36c ++++ 36d + 36e ++ 36f +++ 36g ++++37 + 38 ++ 39a ++ 39b + 39c + 39d + 39e ++ 40 ++ 41a ++ 41b ++ 41c +41d + 42a ++++ 42b +++ 43 + 44 ++ 45 +++ 46 + 47 ++ 48 ++ 49 ++++ 50 +++51 ++++ 52a ++++ 52b ++++ 53 ++++ 54a ++++ 54b +++ 54c ++++ 54d +++ 54e+++ 54f ++++ 54g +++ 54h + 54i + 54j +++ 54k +++ 54l + 54m ++ 55a +++55b ++++ 55c +++ 55d ++++ 55e +++ 55f +++ 55g ++ 55h +++ 55i ++++ 55j+++ 55k +++ 55l +++ 55m ++++ 55n ++ 55o +++ 55p +++ 55q ++++ 55r +++ 55s++++ 55t +++ 55u +++ 55v ++++ 55w ++++ 55x +++ 55y +++ 55z +++ 55aa +++55ab +++ 55ac +++ 55ad +++ 55ae ++ 55af ++ 55ag +++ 55ah +++ 55ai ++++55aj +++ 55ak ++ 55al +++ 55am +++ 55an +++ 55ao +++ 55ap +++ 55aq +++55ar +++ 55as +++ 55at +++ 55au +++ 55av +++ 55aw ++ 55ax +++ 55ay ++55az ++++ 55ba ++++ 55bb ++++ 55bc ++++ 55bd ++++ 55be ++++ 55bf +++55bg ++++ 55bh +++ 55bi ++++ 55bj ++++ 55bk +++ 55bl ++ 55bm ++ 55bn +55bo +++ 55bp +++ 55bq ++ 55br ++ 55bs ++ 55bt ++ 55bu ++ 55bv ++ 55bw+++ 55bx ++ 55by ++ 55bz +++ 55ca +++ 55cb +++ 55cc +++ 55cd ++ 55ce ++55cf + 55cg ++ 55ch +++ 55ci ++ 55cj ++ 55ck ++ 55cl +++ 55cm ++ 55cn ++55co +++ 55cp ++ 55cq +++ 55cr ++ 55cs ++ 55ct ++ 55cu ++ 55cv ++ 55cw++ 55cx ++ 55cy ++ 55cz +++ 55da ++ 55db ++ 55dc ++++ 55dd +++ 55de +++55df +++ 55dg +++ 55dh +++ 55di +++ 55dj +++ 55dk +++ 55dl +++ 55dm +++55dn +++ 55do ++++ 55dp ++++ 55dq ++++ 56 +++ 57 +++ 58 +++ 59 ++ 59b ++59c +++ 59d +++ 60 ++ 61 +++ 62 +++PheOH and TH Inhibition Counter Assays

Certain compounds of the Examples were found to inhibit tryptophanhydroxylase (TPH) selectively over phenylalanine hydroxylase (PheOH)Inhibitory activity against PheOH can be assessed according to themethods described for example in J. Med. Chem. 10, 64-66 (1967), or J.Antibiot. 35, 458-462 (1982), or WO 2007/089335.

Certain compounds of the invention were found to inhibit tryptophanhydroxylase (TPH) selectively over tyrosine hydroxylase (TH). Inhibitoryactivity against TH can be assessed according to the methods describedfor example in Life Sci. 39, 2185-2189 (1986), or Mol. Pharmacol. 41,339-344 (1992), or J. Antibiot. 35, 458-462 (1982), or WO 2007/089335.

Example B: Intestinal 5-HT Depletion Assay

The efficacy of the TPH1 inhibitors of the invention was assessed forthe ability to decrease intestinal serotonin concentration in mice. Mice(C57 BL6) were administered a single 150 mg/kg dose of test article byoral gavage. Each animal was euthanized by exsanguination underisoflurane anesthesia. Jejunal intestinal mucosa was isolated andhomogenized in 300 μL of a buffer containing 0.3M trichloroacetic acid,0.1M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate and 50 mMascorbic acid. Following centrifugation the 5-HT levels in thesupernatants were measured by HPLC. The remaining mucosal pellet wassolubilized overnight at 37° C. in a 0.1% sodium dodecyl sulfate bufferin 0.1N NaOH followed by determination of protein concentrations using aBCA protein assay (Pierce, Rockford, Ill. 5-HT levels were normalized toprotein and data were expressed as mean percent reduction of mucosal5-HT levels relative to vehicle control±SEM (percent 5-HT reduction).All animal studies were carried out with protocols approved by theInstitutional Animal Care and Use Committee.

The Examples listed in Table 26 below were tested and found to elicit areduction in mean mucosal 5-HT concentrations relative tovehicle-treated animals according to the above-described in vivo assay.P-values, indicating statistical significance of the data (ANOVA) areprovided in the table: * refers to P<0.05, ** refers to P<0.01, ***refers to P<0.005, and **** refers to P<0.0005.

TABLE 26 In Vivo Efficacy of TPH1 Inhibitors In Mice (reduction ofmucosal 5-HT concentrations one day after oral administration of asingle 150 mg/kg dose) Example No. Efficacy  1g ***  1h **  1l ****  1m***  1n **  1o **  1p **  1y **  5 **  10b ***  10d ***  10g **  10h *** 10j ****  10k *  1l ****  12b *  12c ***  16 **  22c *  28 *  29z ** 31 *  34r ***  34s **  34u *  34v *  34w ***  55k *  55ak **  55al * 55am ***  55an ***  55az ***  55bc **  55bd ***  55bg ***  63g *** 63ay ***  63az ***   63ba ***  63bd ***  63be ***  63bf ****  63bg **** 63bh **  63bi **  63bn ****  63bo ****  63bp ****  63bq ****  63bx *** 63by ***  63bz **  63ch ***  63cj ***  63cl ***  63cp ***  63da *** 63dc ***  63di ***  64c ****  64e ****  64f ****  64g *  64h **  65a****  66c ****  66d **** 101 ***

Example C: Reduction of Mucosal 5-HT Concentrations

The Examples listed in Table 27 below were tested and found to elicit areduction in mean mucosal 5-HT concentrations relative tovehicle-treated animals according to the following in vivo assay.

The efficacy of the TPH1 inhibitors of the invention was assessed forthe ability to decrease intestinal serotonin concentration in mice. Mice(C57 BL6) were administered an oral dose of 10 or 50 mg/kg of the testarticle in the evening. Approximately 16 h following the first dose,mice were administered a second oral dose of 50 mg/kg of the appropriatecompound. A third oral dose of 50 mg/kg of the appropriate test articlewas administered 12 h after dose 2. Following an overnight fast, eachanimal was euthanized by exsanguination under isoflurane anesthesia.Jejunal intestinal mucosa was isolated and homogenized in 300 mL of abuffer containing 0.3M trichloroacetic acid, 0.1M sodium acetate, 10 mMEDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. Followingcentrifugation the 5-HT levels in the supernatants were measured byHPLC. The remaining mucosal pellet was solubilized overnight at 37° C.in a 0.1% sodium dodecyl sulfate buffer in 0.1N NaOH followed bydetermination of protein concentrations using a BCA protein assay(Pierce, Rockford, Ill.). 5-HT levels were normalized to protein anddata were expressed as mean percent reduction of mucosal 5-HT levelsrelative to vehicle control±SEM (percent 5-HT reduction). All animalstudies were carried out with protocols approved by the InstitutionalAnimal Care and Use Committee. P-values, indicating statisticalsignificance of the data (ANOVA) are provided in the table: * refers toP<0.05, ** refers to P<0.01, *** refers to P<0.005, and **** refers toP<0.0005.

TABLE 27 In Vivo Efficacy of TPH1 Inhibitors In Mice (reduction ofmucosal 5-HT concentrations two days after oral administration of asingle 50 mg/kg dose) Example No. Efficacy  1l ***  1m *  1n ***  1t ***12c *** 55bg *** 63i *** 63ae *** 63aq *** 63ar **** 63aw **** 63az ***63bd *** 63bf *** 63bg *** 63bn **** 63bo *** 63bp *** 63ch *** 63cj **63cl *** 63cn **** 63dc *** 63el *** 63eo *** 63ep *** 63ev *** 63ey **63fo * 63ha ** 64hb *** 69a *** 69b *** 69c ***

Example D: In Vivo Assay for Inflammatory Bowel Diseases

The utility of the compounds of the invention for the treatment ofinflammatory bowel diseases can be measured, for example, using theexperimental models of colitis induced by trinitrobenzene sulfonic acid(TNBS), dinitrobenzene sulfonic acid (DNBS), and dextran sodium sulfate(DSS), as described by Ghia, J.-E. et al. in Gastroenterol. 137, 1649-60(2009).

Example E: In Vivo Assay for Low Bone Mass Diseases

The utility of the compounds of the invention for the treatment of lowbone mass diseases, such as osteoporosis, can be measured, for example,using the ovariectomy-induced osteopenia rat model, as described byYadav, V. K. et al. in Nature Med. 16, 308-12 (2010).

Example F: In Vivo Assay for PAH

The utility of the compounds of the invention for the treatment ofpulmonary arterial hypertension (PAH), can be measured, for example,using the hypoxia mouse model, as described by Abid, S. et al. in Am. J.Physiol., Lung Cellular and Molecular Physiology 303, L500-8 (2012), orusing the rat monocrotaline-induced PAH or the rat chronic hypoxiamodel, as described by Kay, J. M. et al. Respiration 47, 48-56 (1985).

Example G: In Vivo Assay for Allergic Airway Inflammation

The utility of the compounds of the invention for the treatment ofallergic airway inflammation, can be measured, for example, using themouse model of allergic asthma, as described by Dürk, T. et al. in Am.J. Respir. Crit. Care Med. 187, 476-485 (2013).

Example H: In Vivo Assay for Gastrointestinal Disorders

The utility of the compounds of the invention for the treatment ofgastrointestinal disorders associated with dysregulation of the GIserotonergic system, such as chemotherapy-induced emesis and irritablebowel syndrome, can be measured, for example, using the a ferret modelof chemotherapy-induced emesis, as described by Liu, Q. et al. in J.Pharmacol. Exp. Ther. 325, 47-55 (2008).

Example I: In Vivo Assay for Tumor Growth

The utility of the compounds of the invention for the treatment of tumorgrowth, can be measured, for example, using the xenograft model ofcholangiocarcinoma tumor growth, as described by Alpini, G. et al. inCancer Res. 68, 9184-93 (2008).

Example J: In Vivo Assay for Leukemia

The utility of the compounds of the invention for the treatment andprevention of leukemia and other cancers of the blood, can be measured,for example, using the mouse leukemia model, the osteoblast-deficientmouse model, or the murine model of acute myeloid leukemia, as describedin WO 2013/074889.

Example K: In Vivo Assay for Atherosclerosis

The utility of the compounds of the invention for the treatment ofatherosclerosis, and the reduction of plasma cholesterol andtriglyceride levels, can be measured, for example, using the Apo E −/−or LDLR −/− mouse models of atherosclerotic plaque development, asdescribed in WO 2012/058598.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A pharmaceutical composition suitable foradministration to a patient by inhalation comprising (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 2. The composition of claim 1, wherein thecomposition is in the form of a powder.
 3. The composition of claim 1,wherein the composition is administered as a spray or aerosol.
 4. Thecomposition of claim 3, wherein the aerosol is administered by a sonicnebulizer.
 5. A method of lowering peripheral serotonin in a patientcomprising administering by inhalation to said patient a composition ofclaim
 1. 6. A method of treating pulmonary arterial hypertension (PAH)in a patient, comprising administering by inhalation to said patient atherapeutically effective amount of a composition of claim
 1. 7. Themethod of claim 6 wherein said PAH is associated pulmonary arterialhypertension (APAH).
 8. A pharmaceutical composition suitable foradministration to a patient by injection or infusion comprising(S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 9. The composition of claim 8, wherein theinjection is subcutaneous, intravenous, or intramuscular.
 10. Thecomposition of claim 8, wherein the composition is suitable foradministration to a patient by infusion.
 11. The composition of claim 8,wherein the composition comprises one or more pharmaceuticallyacceptable sterile isotonic aqueous or non-aqueous solutions,dispersions, suspensions or emulsions.
 12. A method of loweringperipheral serotonin in a patient comprising administering by injectionor infusion to said patient a composition of claim
 8. 13. A method oftreating pulmonary arterial hypertension (PAH) in a patient, comprisingadministering by injection or infusion to said patient a therapeuticallyeffective amount of a composition of claim
 8. 14. The method of claim 13wherein said PAH is associated pulmonary arterial hypertension (APAH).15. A pharmaceutical composition suitable for topical administration toa patient comprising (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 16. The composition of claim 15, wherein thecomposition is administered in the form of a powder, spray, ointment,paste, cream, lotion, gel, solution, or patch.
 17. A method of loweringperipheral serotonin in a patient comprising topically administering tosaid patient a composition of claim
 15. 18. A method of treatingpulmonary arterial hypertension (PAH) in a patient, comprising topicallyadministering to said patient a therapeutically effective amount of acomposition of claim
 15. 19. The method of claim 18 wherein said PAH isassociated pulmonary arterial hypertension (APAH).
 20. A pharmaceuticalcomposition suitable for oral administration to a patient comprising(S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 21. The composition of claim 20, wherein thecomposition is prepared in the form of a capsule, a tablet, a pill, adragee, a powder, or granules.
 22. A method of lowering peripheralserotonin in a patient comprising orally administering to said patient acomposition of claim
 20. 23. A method of treating pulmonary arterialhypertension (PAH) in a patient, comprising orally administering to saidpatient a therapeutically effective amount of a composition of claim 20.24. The method of claim 23 wherein said PAH is associated pulmonaryarterial hypertension (APAH).
 25. A method of treating pulmonaryarterial hypertension (PAH) in a patient, comprising administering tosaid patient a therapeutically effective amount of (S)-ethyl8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate,or a pharmaceutically acceptable salt thereof.
 26. The method of claim25 wherein said PAH is associated pulmonary arterial hypertension(APAH).